Microwave synthesis of some new antimicrobial and antiproliferative butenamides and pyrrolidine-2,5-diones

Article abstract of DOI:10.3906/kim-1007-807

Microwave irradiation, comparable to conventional thermal heating, proves to be a convenient method in assisting the synthesis of some butenamides, pyrrolidine-2,5-diones, and their benzenesulfonamido derivatives, which are known to have biological activities and wide medical and industrial applications. Both procedures were used to compare their efficiency in synthesizing butenamides and pyrrolidine-2,5-diones (2-25), which have important and wide applications, from condensation of α,β-unsaturated anhydride (1) with the corresponding amines. Some of the products showed biological or cytotoxic (antiproliferative) activity. TUeBITAK.

Full text of DOI:10.3906/kim-1007-807

Turk J Chem
35 (2011) , 463 – 474.
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˙
c
ꢀ TUBITAK
doi:10.3906/kim-1007-807
Microwave synthesis of some new antimicrobial and
antiproliferative butenamides and pyrrolidine-2,5-diones
Shadia Mahmoud ABDALLAH∗, Halima Aly HEFNY
Department of Chemistry, University College of Women for Arts, Science, and Education,
Ain Shams University, Asma Fahmy Street, Heliopolis-11341, Cairo-EGYPT
e-mail: shadiamabdallah@yahoo.com
Received: 20.07.2010
Microwave irradiation, comparable to conventional thermal heating, proves to be a convenient method
in assisting the synthesis of some butenamides, pyrrolidine-2,5-diones, and their benzenesulfonamido deriva-
tives, which are known to have biological activities and wide medical and industrial applications. Both
procedures were used to compare their efficiency in synthesizing butenamides and pyrrolidine-2,5-diones (2-
25), which have important and wide applications, from condensation of α,β -unsaturated anhydride (1) with
the corresponding amines. Some of the products showed biological or cytotoxic (antiproliferative) activity.
Key Words: Microwave, butenamides, pyrrolidines, sulfonamides, biological activity, antiproliferative
activity
Introduction
In the past few years, there has been exponentially growing attention paid to the use of microwave irradiation
in organic synthesis. It proves to be a convenient method of heating, comparable to conventional thermal tech-
niques, since it is clean and cheap and often results in higher yields with a shorter reaction time. Moreover, some
reactions that do not take place by conventional thermal heating techniques or give low yields can be accom-
plished in high yields with microwave irradiation techniques. It is becoming an increasingly popular method of
heating in industry, pharmaceutical applications, and academia.1−6 The microwave irradiation of 3-carboxy-4-
aryl-3-butenoic acid, 2-arylmethylenebutanedioic anhydride, and methyl 3-carboxy-4-aryl-3-butenoate with dif-
ferent hydrazines or aliphatic or aromatic amines gave 1,2-bis substituted hydrazines, hydrazides, butenamides,
∗Corresponding author
463

Microwave synthesis of some new antimicrobial..., S. M. ABDALLAH, H. A. HEFNY
and/or butanimides in excellent yields and high purity in a short amount of time. Comparison with the conven-
tional heating method showed that microwave heating is more convenient and promising.7 The rapid synthesis
of N-aryl imides from homophthalic anhydride or (4-methoxyphenyl)-5H-pyran-2,6-dione and aromatic amines
under microwave irradiation using natural alumina as solid support in dry reaction conditions resulted in the in-
creased purity of the products in shorter reaction times.8 Microwave synthesis of imides from dicarboxylic acids
with different amines, in one-pot reactions and in the absence of solvents, has been reported.9 The conventional
thermal condensation of γ-phenylitaconic anhydrides with hydrazine hydrate or aromatic or aliphatic amines
gave the corresponding γ-aryl itaconic hydrazide, γ-aryl itaconamic acid, and γ-aryl itaconimide, respectively.
The importance of the synthesized compounds was due to their biological activities.10 The aim of the present
work was to synthesize some new antimicrobial and antiproliferative butenamides and pyrrolidine-2,5-diones
with high yield and purity in a short amount of time, and also to compare the microwave irradiation technique
with conventional thermal heating.
Experimental
General remarks
Microwave irradiation was carried out in a Galanz microwave oven (WP1000AP30-2) at the Chemistry Depart-
ment of the University College of Women for Arts, Science, and Education of Ain Shams University. Spectral
measurements were carried out at the Micro Analytical Center, Faculty of Science of Cairo University, using:
(a) FTIR: PerkinElmer 1430 Infrared Spectrophotometer.
(b) MS spectra: GCMS QP 1000 EX Shimadzu.
(c) 1 H-NMR spectra: Varian Gemini (200 MHz).
(d) Biological activity: Antimicrobial screening was performed in the Botany Department of the Uni-
versity College of Women for Arts, Science, and Education of Ain Shams University, Asma Fahmy Street,
Heliopolis, Cairo, Egypt.
(e) Antiproliferative activity measurements were carried out at the National Institute of Cancer of Cairo
University, Cairo, Egypt.
General solvent-free microwave irradiation technique
In an open vessel, a homogenous, ground mixture of 2-diphenylmethylenebutanedioic anhydride (1)11 with
N-substituted 4-aminobenzenesulfonamides12 a-g or amines h-m was dry irradiated for 2-5 min in a microwave
oven (1000 W, 100% power). The reaction progress was monitored by thin layer chromatography (TLC) until
no more unreacted materials were observed. The reaction mixture was then cooled to room temperature
and dissolved in chloroform. The chloroform layer was washed with diluted HCl to get rid of unreacted
amines, and then extracted with a 10% ice-cold sodium carbonate solution. Acidification of the aqueous
layer with ice-cold concentrated hydrochloric acid precipitated the carboxylic compounds, N-(Nꢀ -substituted
benzenesulfonamido)-3-carboxy-4-aryl-3-butenamide derivatives. Thorough washing of the organic layer with
464

Microwave synthesis of some new antimicrobial..., S. M. ABDALLAH, H. A. HEFNY
water was followed by drying over anhydrous sodium sulfate and organic solvent distillation, which gave N-(Nꢀ -
substituted benzenesulfonamido)-3-substituted pyrrolidine-2,5-dione derivatives. The products obtained were
crystallized from ethanol.
General conventional thermal heating technique
A homogenous mixture of α,β-unsaturated anhydride (1)11 with N-substituted 4-aminobenzenesulfonamides12
a-g (1:2) and amines h-m was heated under reflux for at least 4 h in ethanol. The reaction progress was
monitored by TLC. The reaction mixture was then concentrated; the precipitate formed was filtered and
dissolved in chloroform and then worked up in the same way as described for the solvent-free microwave
irradiation technique. Structures of the products were confirmed by spectral analyses, FTIR, 1 H-NMR, and
MS.
Biological activity: Antimicrobial screening
The antimicrobial screening of the N-[Nꢀ -(4-substituted phenyl)benzenesulfonamido]-3-carboxy-4,4-diphenyl-3-
butenamides and N-[Nꢀ -(4-substituted phenyl)benzenesulfonamido]-3-diphenylmethylenepyrrolidine-2,5-diones,
using the disk diffusion method and inhibition zone diameter (mm/1 cm sample) in DMSO as a solvent, showed
that all derivatives were highly active toward gram-positive and gram-negative bacteria, Staphylococcus aureus
and Escherichia coli, respectively. Some compounds were also highly active toward fungi Aspergillus flavus and
Candida albicans.
Butenamides showed higher biological activity than their corresponding pyrrolidine-2,5-diones. This can
be ascribed to the presence of the carboxyl group. Moreover, compounds containing the electron-withdrawing
chlorine atom or a nitro group showed higher biological activities than the others.
Medicinal application: Antiproliferative activity
Cytotoxic activity compounds 2, 3, 16, and 24, and 5-fluorouracil (5-fluoro-1H-pyrimidine-2,4-dione) as a
reference drug, were tested against human breast carcinoma cell line MCF-7. The method applied was similar
to that reported by Skehan et al.13 The results obtained showed that compounds 2, 3, and 16 had low activity
(3.68, 4.86, and 3.12 μg/mL IC50, respectively), whereas compound 24 was the most active (2.98 μg/mL IC50)
compared to reference drug 5-fluorouracil (0.67 μg/mL IC50), where IC50 is defined as the concentration that
results in a 50% decrease in cell number as compared with that of the control structures in the absence of an
inhibitor.
N-(Nꢀ -Phenylbenzenesulfonamido)-3-carboxy-4,4-diphenyl-3-butenamide (2): White crystals,
mp 142 ˚C, 0% yield in microwave and 14% yield in thermal. FTIR (KBr): υ (cm−1) = 3394-3256 (2NH),
3400-2400 (OH, acid), 1702 (CO, acid), 1688 (CO, amide), and 1340 and 1156 (SO2 , asy. and sym.). MS:
m/z = 512 (M+ , 0%, C29 H24 N2 O5 S), 495 (82.4, C29 H23 N2 O4 S), 494 (100, C29 H22 N2 O4 S), 339 (21.5,
C23 H17 NO2), 338 (83.1, C23 H16 NO2), 219 (12.9, C16 H11 O), 193 (8.3, C15 H13), 191 (71.8, C15 H11), 156
(13.2, C6 H6 NO2 S), 115 (11.3, C9 H7), and 92 (32.8, C6 H6 N).
N-(Nꢀ -Phenylbenzenesulfonamido)-3-diphenylmethylenepyrrolidine-2,5-dione (3): Pale yel-
low crystals, mp 251 ˚C, 71% yield in microwave and 0% yield in thermal. FTIR (KBr): υ (cm−1) = 3189.3
465

Microwave synthesis of some new antimicrobial..., S. M. ABDALLAH, H. A. HEFNY
(NH), 1774-1699 (2CO, imide), and 1379 and 1161 (SO2 , asy. and sym.). MS: m/z = 494 (M+ , 100%,
C29 H22 N2 O4 S), 402 (24.2, C23 H16 NO4 S), 339 (29.2, C23 H17 NO2), 338 (95.9, C23 H16 NO2), 310 (42.6,
C22 H16 NO), 232 (8, C12 H10 NO2 S), 220 (14.9, C16 H12 O), 219 (18.8, C16 H11 O), 191 (77.7, C15 H11), 115
(16.4, C9 H7), and 92 (49.8, C6 H7 N). 1 H-NMR (DMSO-d6): δ (ppm) = 7.06-7.53 (10H, m, 2C6 H5), 3.62
(2H, s, CH2), 7.85-7.89 (2H, d, PhSO2), 7.49-7.53 (2H, d, PhNCO), 10.42 (1H, s, SO2 NH), and 7.32 (5H, s,
C6 H5).
N-[Nꢀ -(4-Methylphenyl)benzenesulfonamido]-3-carboxy-4,4-diphenyl-3-butenamide (4):
White crystals, mp 121 ˚C, 0% yield in microwave and 22% yield in thermal. FTIR (KBr): υ (cm−1) = 3350-
3250 (2NH), 3400-2400 (OH, acid), 1700 (CO, acid), 1686.3 (CO, amide), and 1329 and 1155 (SO2 , asy. and
sym.). MS: m/z = 526 (M+ , 0%, C30 H26 N2 O5 S), 509 (39.4, C30 H25 N2 O4 S), 508 (53.1, C30 H24 N2 O4 S),
339 (46.9, C23 H17 NO2), 338 (40.4, C23 H16 NO2), 191 (49.6, C15 H11), 107 (12.2, C7 H9 N), 106 (100, C7 H8 N),
92 (7, C7 H8), and 91 (4.5, C7 H7). 1 H-NMR (DMSO-d6): δ (ppm) = 7.28-7.34 (10H, m, 2C6 H5), 3.20-3.80
(2H, imp., CH2), 10.37 (1H, s, NHSO2), 7.66 (4H, s, NHC6 H4 SO2), 9.68 (1H, s, NHCO), 7.12-7.34 (2H, d,
NHPh), 6.98-7.01 (2H, d, PhCH3), 2.18-2.19 (3H, s, CH3), and 12.20-12.40 (1H, broad, COOH).
N-[Nꢀ -(4-Methylphenyl)benzenesulfonamido]-3-diphenylmethylenepyrrolidine-2,5-dione (5):
Pale yellow crystals, mp 160 ˚C, 85% yield in microwave and 42% yield in thermal. FTIR (KBr): υ (cm−1
)
= 3248.5 (NH), 1778-1709 (2CO, imide), and 1334 and 1159 (SO2 , asy. and sym.). MS: m/z = 508 (M+ ,
73.3%, C30 H24 N2 O4 S), 339 (36.4, C23 H17 NO2), 338 (30.4, C23 H16 NO2), 310 (11.2, C22 H16 NO), 219 (8.6,
C16 H11 O), 156 (2.3, C6 H6 NO2 S), 115 (7.4, C9 H7), 106 (100, C7 H8 N), and 92 (2.6, C6 H6 N).
N-[Nꢀ -(4-Methoxyphenyl)benzenesulfonamido]-3-carboxy-4,4-diphenyl-3-butenamide (6):
White crystals, mp 196 ˚C, 0% yield in microwave and 29% yield in thermal. FTIR (KBr): υ (cm−1) = 3287-
3235 (2NH), 3400-2400 (OH, acid), 1700 (CO, acid), 1671 (CO, amide), and 1331 and 1160 (SO2 , asy. and
sym.). MS: m/z = 542 (M+ , 0%, C30 H26 N2 O6 S), 525 (9.1, C30 H25 N2 O5 S), 524 (23.7, C30 H24 N2 O5 S), 339
(7, C23 H17 NO2), 338 (10.5, C23 H16 NO2), 192 (11.3, C15 H12), 191 (22.3, C15 H11), 123 (10, C6 H5 NS), 122
(100, C7 H8 NO), and 115 (2.7, C9 H7). 1 H-NMR (DMSO-d6): δ (ppm) = 7.92-7.38 (10H, m, 2C6 H5), 3.44
(2H, s, CH2), 10.37 (1H, s, NHSO2), 7.67 (2H, d, PhSO2), 7.59-7.63 (2H, d, PhNCO), 9.81 (1H, s, NHCO),
6.96-6.99 (2H, d, NHPh), 6.78-6.83 (2H, d, PhOCH3), 3.67 (3H, s, OCH3), and 12.2-12.4 (1H, broad, COOH).
N-[Nꢀ -(4-Methoxyphenyl)benzenesulfonamido]-3-diphenylmethylenepyrrolidine-2,5-dione (7):
Pale brown crystals, mp 103 ˚C, 87% yield in microwave and 41% yield in thermal. FTIR (KBr): υ (cm−1
)
= 3249 (NH), 1774-1710 (2CO, imide), and 1335 and 1159 (SO2, asy. and sym.). MS: m/z = 524 (M+ , 31.6%,
C30 H24 N2 O5 S), 338 (4, C23 H16 NO2), 310 (4, C22 H16 NO), 219 (2.3, C16 H11 O), 193 (1.6, C15 H13), 192 (6,
C
15 H12), 191 (14.6, C15 H11), 123 (8.2, C6 H5 NS), 122 (100, C7 H8 NO), and 108 (2.1, C7 H8 O). 1 H-NMR
(DMSO-d6): δ (ppm) = 7.10-7.52 (10H, m, 2C6 H5), 3.39 (2H, s, CH2), 7.47-7.52 (2H, d, PhNCO), 7.78-7.82
(2H, d, PhSO2), 10.07 (1H, s, NHSO2), 6.99-7.04 (2H, d, NHPh), 6.71-6.83 (2H, d, CH3 OPh), and 3.62 (3H,
s, OCH3).
N-[Nꢀ -(4-Chlorophenyl)benzenesulfonamido]-3-carboxy-4,4-diphenyl-3-butenamide (8):
White crystals, mp 149 ˚C, 22% yield in microwave and 43% yield in thermal. FTIR (KBr): υ (cm−1
)
= 3381-3235 (2NH), 3400-2400 (OH, acid), 1701.6 (CO, acid), 1678 (CO, amide), and 1327 and 1160 (SO2 ,
asy. and sym.). MS: m/z =546 (M+ , 0%, C29 H23 N2 O5 SCl), 528 (68.6, C29 H21 N2 O4 SCl), 402 (38.75,
C23 H16 NO4 S), 339 (50.4, C23 H17 NO2), 338 (100, C23 H16 NO2), 219 (10.5, C16 H11 O), 192 (36.3, C15 H12),
466

Microwave synthesis of some new antimicrobial..., S. M. ABDALLAH, H. A. HEFNY
191 (52.3, C15 H11), 310 (22.8, C22 H16 NO), and 127 (22.3, C6 H6 NCl).
N-[Nꢀ -(4-Chlorophenyl)benzenesulfonamido]-3-diphenylmethylenepyrrolidine-2,5-dione (9):
Pale yellow crystals, mp 99 ˚C, 50% yield in microwave and 0% yield in thermal. FTIR (KBr): υ (cm−1
)
= 3246.6 (NH), 1771-1709 (2CO, imide), and 1378 and 1161 (SO2 , asy. and sym.). MS: m/z = 528 (M+ ,
100%, C30 H24 N2 O5 S), 402 (41.8, C23 H16 NO4 S), 339 (20.1, C23 H17 NO2), 338 (97.3, C23 H16 NO2), 310
(25.4, C22 H16 NO), 193 (5, C15 H13), 192 (46, C15 H12), 191 (61.3, C15 H11), 126 (30.2, C6 H5 NCl), and 115
(16.2, C9 H7).
N-[Nꢀ -(4-Nitrophenyl)benzenesulfonamido]-3-carboxy-4,4-diphenyl-3-butenamide (10): Whi-
te crystals, mp 160 ˚C, 34% yield in microwave and 62% yield in thermal. FTIR (KBr): υ (cm−1) = 3398-3203
(2NH), 3400-2400 (OH, acid), 1701.8 (CO, acid), 1686 (CO, amide), and 1353 and 1149 (SO2 , asy. and sym.).
MS: m/z = 557 (M+ , 0%, C29 H23 N3 O7 S), 402 (41.5, C23 H16 NO4 S), 338 (80.8, C23 H16 NO2), 191 (100,
C15 H11), 156 (33.7, C6 H6 NO2 S), 122 (18.1, C6 H4 NO), 115 (17.6, C9 H7), and 92 (31.6, C6 H6 N).
N-[Nꢀ -(4-Nitrophenyl)benzenesulfonamido]-3-diphenylmethylenepyrrolidine-2,5-dione (11):
Brown crystals, mp 111 ˚C, 46% yield in microwave and 0% yield in thermal. FTIR (KBr): υ (cm−1
)
= 3247 (NH), 1770-1712 (2CO, imide), and 1348 and 1128 (SO2 , asy. and sym.). MS: m/z = 539 (M+ ,
2.4%, C29 H21 N3 O6 S), 402 (1.5, C23 H16 NO4 S), 339 (2.4, C23 H17 NO2), 219 (2.4, C16 H11 O), 292 (1.5,
C12 H10 NO4 S), 193 (0.6, C15 H13), 143 (17.3, C10 H7 O), 142 (100, C10 H6 O), 138 (2.4, C6 H6 N2 O2), and 115
(70, C9 H7).
N-[Nꢀ -(1-Naphthyl)benzenesulfonamido]-3-carboxy-4,4-diphenyl-3-butenamide (12): White
crystals, mp 160 ˚C, 66% yield in microwave and 66% yield in thermal. FTIR (KBr): υ (cm−1) = 3396-3249.6
(2NH), 3400-2400 (OH, acid), 1701.5 (CO, acid), 1680 (CO, amide), and 1399 and 1156 (SO2 , asy. and sym.).
MS: m/z = 562 (M+ , 0%, C33 H26 N2 O5 S), 545 (48.5, C33 H25 N2 O4 S), 544 (28.9, C33 H24 N2 O4 S), 338 (10,
C23 H16 NO2), 298 (11.8, C16 H14 N2 O2 S), 219 (11.5, C16 H11 O), 193 (2.6, C15 H13), 192 (24, C15 H12), 191
(27.3, C15 H11), 142 (79.9, C10 H9 N), and 115 (100, C9 H7).
N-[Nꢀ -(1-Naphthyl)benzenesulfonamido]-3-diphenylmethylenepyrrolidine-2,5-dione (13): Vi-
olet crystals, mp 92 ˚C, 19% yield in microwave and 0% yield in thermal. FTIR (KBr): υ (cm−1) = 3241
(NH), 1766-1705.7 (2CO, imide), and 1301 and 1150 (SO2 , asy. and sym.). MS: m/z = 544 (M+ , 13.8%,
C23 H24 N2 O4 S), 390 (1.8, C32 H25 N2 O3 S), 389 (4.2, C32 H24 N2 O3 S), 193 (2.1, C15 H13), 192 (10.6, C15 H12),
191 (8, C15 H11), 156 (25.9, C6 H6 NO2 S), 142 (70.2, C10 H8 N), 115 (100, C9 H7), and 92 (24, C6 H6 N).
N-(Nꢀ -Benzylbenzenesulfonamido)-3-carboxy-4,4-diphenyl-3-butenamide (14): White crys-
tals, mp 130 ˚C, 92% yield in microwave and 62% yield in thermal. FTIR (KBr): υ (cm−1) = 3316-3250
(2NH), 3400-2400 (OH, acid), 1700 (CO, acid), 1686 (CO, amide), and 1321 and 1154 (SO2 , asy. and sym.).
MS: m/z = 526 (M+ , 0%, C30 H26 N2 O5 S), 264 (49.4, C17 H14 NO2), 262 (35.2, C13 H14 N2 O2 S), 508 (29.2,
C30 H24 N2 O4 S), 192 (73.8, C15 H12), 191 (60.5, C15 H11), 156 (21.4, C6 H6 NO2 S), 115 (10.8, C9 H7), 106
(69.6, C7 H8 N), 93 (100, CH3 NO2 S), and 91 (45.2, C7 H7). 1 H-NMR (DMSO-d6): δ (ppm) = 7.16-7.40
(10H, m, 2 C6 H5), 3.46 (2H, s, CH2 CO), 10.39 (1H, s, NHCO), 7.76 (4H, s, NHC6 H4 SO2), 8.01-8.08 (1H, t,
NHCH2), 3.94-3.97 (2H, d, CH2 NH), 7.29 (5H, s, CH2 C6 H5), and 12.2-12.40 (1H, broad, COOH).
N-(4-Methylphenyl)-3-carboxy-4,4-diphenyl-3-butenamide (15): Pale yellow crystals, mp 191
˚C, 0% yield in microwave and 71% yield in thermal. FTIR (KBr): υ (cm−1) = 3400 (NH, amide), 3400-2400
(OH, acid), 1710 (CO, acid), and 1640 (CO, amide). MS: m/z = 371 (M+ , 2.6%, C24 H21 NO3), 353 (2.8,
467

Microwave synthesis of some new antimicrobial..., S. M. ABDALLAH, H. A. HEFNY
24 H19 NO2), 264 (3.8, C17 H12 O3), 192 (20.5, C15 H12), and 107 (100, C7 H9 N). 1 H-NMR (DMSO-d6):
C
δ (ppm) = 7.20-7.40 (10H, m, 2C6 H5), 3.28 (2H, imp., CH2), 7.41-7.43 (2H, d, NHPh), 6.96-6.99 (2H, d,
CH3 Ph), 2.19 (3H, s, CH3), and 9.33 (1H, s, CONHPh).
N-(4-Methylphenyl)-3-diphenylmethylenepyrrolidine-2,5-dione (16): White crystals, mp 172
˚C, 95% yield in microwave and 15% yield in thermal. FTIR (KBr): υ (cm−1) = 1760-1703 (2CO, imide).
MS: m/z = 353 (M+ , 44%, C24 H19 NO2), 192 (100, C15 H12), 191 (58, C15 H11), and 115 (11, C9 H7). 1 H-
NMR (DMSO-d6): δ (ppm) = 7.20-7.40 (10H, m, 2C6 H5), 3.59 (2H, s, CH2), 7.45-7.46 (2H, d, CONPh),
7.14-7.15 (2H, d, CH3 Ph), and 2.33 (3H, s, CH3).
N-(4-Methoxyphenyl)-3-carboxy-4,4-diphenyl-3-butenamide (17): Gray crystals, mp 156 ˚C,
0% yield in microwave and 41% yield in thermal. FTIR (KBr): υ (cm−1) = 3350 (NH, amide), 3400-2500
(OH, acid), 1700 (CO, acid), and 1640 (CO, amide). MS: m/z = 387 (M+ , 15%, C24 H21 NO4), 369 (26,
C
24 H19 NO3), 264 (9, C17 H12 O3), 192 (58, C15 H12), and 123 (100, C7 H9 NO). 1 H-NMR (DMSO-d6): δ
(ppm) = 7.14-7.39 (10H, m, 2C6 H5), 3.59 (2H, s, CH2), 6.60-6.63 (2H, d, NHPh), 6.48-6.51 (2H, d, CH3 OPh),
3.66 (3H, s, OCH3), and 9.27 (1H, s, CONHPh).
N-(4-Methoxyphenyl)-3-diphenylmethylenepyrrolidine-2,5-dione (18): Dark gray crystals, mp
192 ˚C, 97% yield in microwave and 14% yield in thermal. FTIR (KBr): υ (cm−1) = 1760-1703 (2CO, imide).
MS: m/z = 369 (M+ , 66%, C24 H19 NO3), 192 (100, C15 H12), 191 (76, C15 H11), and 115 (13, C9 H7). 1 H-
NMR (DMSO-d6): δ (ppm) = 7.19-7.42 (10H, m, 2C6 H5), 3.55 (2H, s, CH2), 7.17-7.18 (2H, d, CONHPh),
6.97-6.98 (2H, d, CH3 OPh), and 3.76 (3H, s, OCH3).
N-(4-Chlorophenyl)-3-carboxy-4,4-diphenyl-3-butenamide (19): Gray crystals, mp 196 ˚C, 0%
yield in microwave and 88% yield in thermal. FTIR (KBr): υ (cm−1) = 3350 (NH, amide), 3400-2500
(OH, acid), 1700 (CO, acid), and 1640 (CO, amide). MS: m/z = 391 (M+ , 2%, C23 H18 NO3 Cl), 373 (3,
C23 H16 NO2 Cl), 264 (23, C17 H12 O3), 192 (100, C15 H12), 127 (91, C6 H6 NCl), and 111 (3, C6 H4 Cl).
N-(4-Chlorophenyl)-3-diphenylmethylenepyrrolidine-2,5-dione (20): Pale brown crystals, mp
150 ˚C, 93% yield in microwave and 0% yield in thermal. FTIR (KBr): υ (cm−1) = 1758.6-1703 (2CO,
imide). MS: m/z = 373 (M+ , 2.1%, C23 H16 NO2 Cl), 375 (M+2 , 1.3%), 262 (3.4, C17 H12 NO2), 192 (4.1,
C15 H12), 130 (100, C9 H6 O), 129 (80, C9 H5 O), 127 (16.1, C6 H6 NCl), 153 (0.5, C7 H4 NOCl), 115 (67.1,
C9 H7), and 111 (1.6, C6 H4 Cl). 1 H-NMR (DMSO-d6): δ (ppm) = 7.54-7.58 (10H, m, 2C6 H5), 3.61 (2H, s,
CH2), 7.24-7.32 (2H, d, ClPh), and 7.36-7.42 (2H, d, CONPh).
N-(4-Nitrophenyl)-3-carboxy-4,4-diphenyl-3-butenamide (21): Yellow crystals, mp 190 ˚C, 0%
yield in microwave and 69% yield in thermal. FTIR (KBr): υ (cm−1) = 3319 (NH, amide), 3400-2500
(OH, acid), 1690 (CO, acid), and 1677 (CO, amide). MS: m/z = 402 (M+ , 0%, C23 H18 N2 O5), 384 (6,
C23 H16 N2 O4), 264 (26, C17 H12 O3), 191 (100, C15 H11), 138 (53, C6 H6 N2 O2), and 115 (46, C9 H7).
N-(4-Nitrophenyl)-3-diphenylmethylenepyrrolidine-2,5-dione (22): Brown crystals, mp 186
˚C, 92% yield in microwave and 0% yield in thermal. FTIR (KBr): υ (cm−1) = 1770-1714 (2CO, imide).
MS: m/z = 3843 (M+ , 28%, C23 H16 N2 O4), 307 (10.3, C17 H11 N2 O4), 231 (5.1, C11 H7 N2 O4), 205 (6.4,
C9 H5 N2 O4), 192 (100, C15 H12), 191 (59.3, C15 H11), 164 (41, C7 H4 N2 O3), and 115 (25.5, C9 H7). 1 H-
NMR (DMSO-d6): δ (ppm) = 7.33-7.43 (10H, m, 2C6 H5), 3.65 (2H, s, CH2), 7.70-7.82 (2H, d, CONPh), and
8.25-8.335 (2H, d, NO2 Ph).
468

Microwave synthesis of some new antimicrobial..., S. M. ABDALLAH, H. A. HEFNY
N-(1-Naphthyl)-3-carboxy-4,4-diphenyl-3-butenamide (23): Violet crystals, mp 212 ˚C, 17%
yield in microwave and 44% yield in thermal. FTIR (KBr): υ (cm−1) = 3249 (NH, amide), 3400-2500 (OH,
acid), 1700 (CO, acid), and 1640 (CO, amide). MS: m/z = 407 (M+ , 0%, C27 H21 NO3), 384 (3, C27 H19 NO2),
264 (2, C17 H12 O3), 192 (15, C9 H8), 143 (100, C10 H9 N), and 115 (32, C9 H7).
N-(1-Naphthyl)-3-diphenylmethylenepyrrolidine-2,5-dione (24): Pale brown crystals, mp 190
˚C, 74% yield in microwave and 0% yield in thermal. FTIR (KBr): υ (cm−1) = 1769-1711 (2CO, imide).
MS: m/z = 389 (M+ , 12.9%, C27 H19 NO2), 220 (2.2, C16 H12 O), 219 (4.3, C16 H11 O), 192 (14.3, C15 H12),
191 (10.3, C15 H11), 143 (27, C10 H9 N), 142 (100, C10 H8 N), 127 (6.5, C10 H7), 115 (73.7, C9 H7), 97 (1.8,
C4 H3 NO2), and 92 (5.4, C6 H6 N).
N-Benzyl-3-carboxy-4,4-diphenyl-3-butenamide (25): Pale blue crystals, mp 162 ˚C, 98% yield
in microwave and 67% yield in thermal. FTIR (KBr): υ (cm−1) = 3284 (NH, amide), 3400-2400 (OH, acid),
1680 (CO, acid), and 1640 (CO, amide). MS: m/z = 371 (M+ , 0%, C24 H21 NO3), 353 (9, C24 H19 NO2), 264
(7, C17 H12 O3), 192 (37, C15 H12), 115 (30, C9 H7), and 91 (100, C7 H7).
Results and discussion
Solvent-free microwave irradiation of anhydride (1) with N-substituted 4-aminoben-
zenesulfonamides (a-g) and amines (h-m)
Solvent-free microwave irradiation of 2-diphenylmethylenebutanedioic anhydride (1) with N-phenyl-4-aminoben-
zenesulfonamide (a), N-(4-methylphenyl)-4-aminobenzenesulfonamide (b), and N-(4-methoxyphenyl)-4-amino-
benzenesulfonamide (c) gave pyrrolidine-2,5-diones 3, 5, and 7, whereas with N-(4-chlorophenyl)-4-aminobenze-
nesulfonamide (d), N-(4-nitrophenyl)-4-aminobenzenesulfonamide (e), and N-(1-naphthyl)-4-aminobenzenesul-
fonamide (f), it gave separable mixtures from corresponding butenamides 8, 10, and 12 and pyrrolidine-2,5-
diones 9, 11, and 13. The formation of the separable mixtures can be ascribed to the low nucleophilicity of
the amido nitrogen atom toward further intramolecular nucleophilic attack on the carbonyl carbon to give the
corresponding pyrrolidine-2,5-diones.
However, reaction with N-benzyl-4-aminobenzenesulfonamide (g) gave butenamide 14 as the only prod-
uct, which could be attributed to the steric effect exerted by the sp3 tetrahedral carbon in the benzyl group in
amine g, irrespective of the coplanarity of the 2 phenyl rings in anhydride 1. The microwave irradiation of an-
hydride 1 with amines 4-methylaniline (h), 4-methoxyaniline (i), 4-chloroaniline (j), and 4-nitroaniline (k) gave
corresponding pyrrolidine-2,5-diones 16, 18, 20, and 22, whereas with 1-naphthylamine (l) it gave a separable
mixture from butenamide 23 and pyrrolidine-2,5-dione 24, and with benzylamine (m) it gave butenamide 25
as the only product, due to the steric effect exerted by the sp3 tetrahedral carbon in the benzyl group (Scheme
1).
In general, the results obtained from microwave irradiation of N-substituted 4-aminobenzenesulfonamides
a-g with anhydride 1 show the low reactivity of the butenamides toward further cyclization, more so than with
amines h-m. This can be attributed to the low basicity of amines a-g due to the presence of benzenesulfonamido
moiety.
469

Microwave synthesis of some new antimicrobial..., S. M. ABDALLAH, H. A. HEFNY
(1)
O
O
O
MW
O
S
R
NH2
m)
R
H2N
NH
(h
O
g)
(a
NH R
O
O
S
R
NH
O
HO
NH
HO
O
O
O
Comp.
8
R
Yield%
27
Comp.
23
25
R
Yield%
12
4-ClC H
1-Naphthyl
C6H4CH2
10
4-NO26C 4H4
1-Napht6hyl
C6H4CH2
34
12
14
66
92
+
O
N
+
O
N
O
O
S
R
NH
R
O
O
Comp.
R
Yield%
71
Comp.
16
R
Yield%
95
3
C6H5
4-CH C H4
5
4-CH C H4
84
18
4-CH33O6C6H4 97
7
4-CH33O6C6H4 96
20
4-ClC H
93
92
74
9
4-ClC H
50
46
19
22
4-NO26C 4H4
11
13
4-NO26C 4H4
24
1-Napht6hyl
1-Napht6hyl
Scheme 1.
470

Microwave synthesis of some new antimicrobial..., S. M. ABDALLAH, H. A. HEFNY
(1)
O
O
O
ermal
O
S
R
R
NH2
m)
H2N
NH
(h
O
g)
(a
NH R
O
O
S
R
NH
O
HO
NH
HO
O
O
O
Comp.
R
Yield%
14
Comp.
15
R
Yield%
15
2
C6H5
4-CH C H4
4
4-CH C H4
22
17
4-CH33O6C6H4 42
6
4-CH33O6C6H4 29
19
4-ClC H
88
69
70
67
8
4-ClC H
44
62
66
62
21
4-NO26C 4H4
1-Napht6hyl
C6H4CH2
10
12
14
4-NO26C 4H4
1-Napht6hyl
C6H4CH2
23
25
+
+
O
O
O
N
R
N
O
S
NH
R
O
O
Comp.
5
7
R
Yield%
41
Comp.
16
18
R
Yield%
71
4-CH C H4
4-CH C H5
4-CH33O6C6H4 42
4-CH33O6C6H5 72
Scheme 2.
471

Microwave synthesis of some new antimicrobial..., S. M. ABDALLAH, H. A. HEFNY
Conventional thermal heating of anhydride (1) with N-substituted 4-aminobenze-
nesulfonamides (a-g) and amines (h-m)
The conventional thermal heating technique for anhydride 1 with amines a and d-g gave butenamides 2, 8, 10,
12, and 14 as the only products, whereas with amines b and c, it gave separable mixtures from corresponding
butenamides 4 and 6 and pyrrolidine-2,5-diones 5 and 7, respectively. The formation of the separable mixtures
can be ascribed to the presence of the electron-donating methyl and methoxyl groups, which increase the basicity
of the amido nitrogen atom toward nucleophilic attack on the carbonyl carbon.
Similarly, the condensation of anhydride 1 with amines h and i gave the corresponding separable mixtures
from butenamides 15 and 17 and pyrrolidine-2,5-diones 16 and 18, respectively, whereas with amines j-m, it
gave corresponding butenamides 19, 21, 23, and 25, respectively, as the only products (Scheme 2).
Comparison between the yields obtained from condensation of anhydride 1 with amines h and i shows
that amines b and c offered low yields due to the presence of benzenesulfonamido moiety (Table).
Table. Comparison of yields of products resulting from the microwave irradiation and conventional thermal heating
techniques.
Product (Yield %)
Amine
Microwave heating
Conventional thermal heating
Butenamide Pyrrolidine-2,5-dione Butenamide Pyrrolidine-2,5-dione
N-Phenyl-4-amino-
benzenesulfonamide
N-(4-Methylphenyl)-4-
aminobenzenesulfonamide
N-(4-Methoxyphenyl)-4-
aminobenzenesulfonamide
N-(4-Chlorophenyl)-4-
aminobenzenesulfonamide
N-(4-Nitrophenyl)-4-
aminobenzenesulfonamide
N-(1-Naphthyl)-4-
-
3; 71%
5; 84%
7; 86%
9; 50%
11; 46%
13; 19%
2; 14%
4; 22%
6; 29%
8; 44%
10; 62%
12; 66%
-
-
5; 41%
-
7; 42%
8; 22%
10; 34%
12; 66%
-
-
-
aminobenzenesulfonamide
N-Benzyl-4-
aminobenzenesulfonamide
4-Methylaniline
14; 92%
-
14; 62%
15; 15%
17; 42%
19; 88%
21; 69%
23; 70%
25; 67%
-
-
16; 95%
18; 97%
20; 93%
22; 92%
24; 74%
-
16; 71%
4-Methoxyaniline
-
18; 72%
4-Chloroaniline
-
-
-
-
-
4-Nitroaniline
-
1-Naphthylamine
23; 17%
25; 98%
Benzylamine
472

Microwave synthesis of some new antimicrobial..., S. M. ABDALLAH, H. A. HEFNY
In general, the butenamides that resulted from amines j-m were in better yields than those produced from
amines d-g (Table).
Structural effect of α,β -unsaturated anhydride on the reactions
Comparison between the products obtained from both the microwave irradiation and conventional ther-
mal heating of anhydride 1, 2-methylphenylmthylenebutanedioic anhydride, or 2-phenylmethylenebutanedioic
anhydride14,15 with different N-substituted 4-aminobenzenesulfonamide derivatives (a-g) or amines (h-m)
shows that the steric factor exerted by the presence of the sp3 carbon of the methyl group in 2-methylphen-
ylmethylenebutanedioic anhydride decreased its reactivity toward cyclization compared to the other 2 anhy-
drides. However, the coplanarity exerted by the 2 phenyl rings in anhydride 1 facilitated the further in-
tramolecular nucleophilic attack of the amido nitrogen atom on the carbonyl carbon to give the corresponding
pyrrolidine-2,5-diones.
Conclusion
In the present work, comparison showed that microwave irradiation accomplishes reactions with excellent yields
and purity and in shorter times, assists cyclization, and shows regiospecific properties much more so than the
conventional thermal heating technique. Furthermore, it proved to be more economical and environmentally
friendly (green chemistry). Both microwave irradiation and conventional thermal heating techniques of N-
substituted 4-aminobenzenesulfonamides with α,β-unsaturated anhydrides showed lower reactivity than the
corresponding nonsulfonated amines, which could be attributed to the presence of the benzenesulfonamido
group.
Acknowledgements
The authors would like to thank the Department of Chemistry of the University College of Women for Arts,
Science, and Education, Ain Shams University.
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474

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