Original Article 473
3,4,5-Trisubstituted Furan-2(5H)-one Derivatives: Efficient one-pot Synthesis and Evaluation of Cytotoxic Activity
Authors
W. M. Basyouni1, Kh. A. M. El-Bayouki1, A. S. El-Sayed2, W. M. Tohamy1, M. M. S. Farag3, M. A. Abd-El-Baseer4
Affiliations
1
Key words ▶ one-pot synthesis ● ▶ furan-2(5H)-one ● ▶ silica sulfuric acid ● ▶ cytotoxicity ●
Abstract
Organometallic and Organometalloid Chemistry Department, National Research Centre, Cairo, Egypt Chemistry Department, Faculty of Science, Al-Azhar University, Cairo, Egypt 3 Botany and Microbiology Department, Faculty of Science, Al-Azhar University, Cairo, Egypt 4 Center for Virus Research and Studies, Al-Azhar University, Cairo, Egypt
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A series of 3,4,5-trisubstituted 2(5H)-furanone derivatives was synthesized through one-pot reaction of amines, aldehydes and diethyl acetylenedicarboxylate. Silica sulfuric acid efficiently catalyzes the 3-component reaction to afford the corresponding 2(5H)-furanones in high yields. The synthesized compounds were tested against
Introduction
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received 24.03.2014 accepted 04.08.2014 Bibliography DOI http://dx.doi.org/ 10.1055/s-0034-1387768 Published online: September 10, 2014 Drug Res 2015; 65: 473–478 © Georg Thieme Verlag KG Stuttgart · New York ISSN 2194-9379 Correspondence W. M. Basyouni Organometallic and Organometalloid Chemistry Department National Research Centre Dokki Cairo 12622 Egypt Tel.: + 202/333/35 994 Fax: + 202/333/70 931 [email protected]
2-Furanone moiety has received considerable attention due to their significant biological activities such as antifungal agents [1, 2]. 2-Furanone moiety is frequently found as a substructure in natural products. The natural furanone such as fimbrolide [3] and their derivatives have possessed antiviral, antibiotic and anticancer activities [4]. Moreover, the synthetic 3,4-diaryl2(5H)-furanones have also been reported as cytotoxic agents [5, 6] and the 3-amino-2(5H) furanones able to block the replication of sub▶ Fig. 1). genomic RNA of HCV in liver cells [7] ( ● Synthesis of 2(5H)-furanone by heating furfural with hydrogen peroxide leading to a mixture of 2(3H)- and 2(5H)-furanones [8]. Chunling Fu et al. [9] developed the synthesis of 4-iodofuran-2(5H)ones from iodolactonisation of allenoates with molecular iodine. Preparation of 3,4-bistributylstannyl 2(5H)-furanones by reacting TBS as well as THP protected butynoate with hexabutylditin in the presence of PdCl2(PPh3)2 leading to substituted acrylate intermediate, which upon treating under a variety of conditions yielded the desired furanone synthon [10]. The 4-(1-alkynyl)-3-chloro (or bromo)-2(5H)-furanones [11] were synthesized by the Pd/Cu-catalyzed Sonogashira reaction involving treatment of 1-alkynes with 3,4-dichloro (or dibromo)-2(5H)-furanone, respectively, in the presence of KF as a base. The above mentioned methods suffer from certain limitations like multi-
HEPG2, MCF7 and CACO tumor cell lines. The cytotoxic activity for the tested compounds showed that: ethyl 2-(4-fluorophenyl)-5-oxo4-(phenylamino)-2,5-dihydrofuran-3-carboxylate exhibited significant antitumor activity against HEPG2 and MCF7 cell lines (IC50 values 0.002 and 0.002 µM, respectively) more than reference drug (IC50 0.007, 0.005 µM).
step strategies, low yields, use of costly metal catalysts and harsh condition. Due to the pharmacological importance, several protocols aimed to improve the synthesis of furan-2(5H)-ones have been reported. However, some of the newer reported methods also suffer from drawbacks such as unsatisfactory yields, cumbersome product isolation procedures and environmental pollution. Therefore, development of a new reagent with a wide range of structure diversity is needed. In view of the recent trends on the catalytic processes towards the development of clean and green chemical processes, investigation of new, less hazardous chemical catalysts has become a priority in synthesis of organic chemistry. As a part of our extensive research program to rapidly assemble novel bioactive compounds under mild conditions, [12–15], it was of interest to synthesize a novel series of 2(5H)-furanone in excellent yield through one-pot synthesis (multi-component reactions) in the presence of inexpensive silica sulfuric acid (SSA), and preliminary evaluation of the cytotoxic property of the synthesized compounds.
Results and Discussion
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In the initial study, when aniline let to react with diethyl acetylenedicarboxylate (DEACD) and 4-fluorobenzaldehyde in absolute ethanol without catalyst (entry 1), it was found that there is
Basyouni WM et al. Furanones as Cytotoxic Agents … Drug Res 2015; 65: 473–478
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2
474 Original Article
O
H2C
C4H9
Ar2
O
O
H 2C
Fimbrolide
NH2
O
O
Ar1
O
Protoanemonin
O
R3
F
F
Table 1 Results of compound 1 with different catalysts and solvents.
1 2 3 4 5 6 7 8 9 10 11 12
Catalyst
Solvent/T
None PPA/SiO2 SiCl4 HClO4SiO2 Me3SiCl SSA SSA SSA SSA SSA SSA SSA
EtOH/rt EtOH/rt CH2Cl2/rt EtOH/rt EtOH/rt MeOH/rt CH3CN/rt CH2Cl2 /rt EtOH/rt EtOH/85◦C EtOH/85◦C EtOH/85◦C
Fig. 2 Optimization of reaction conditions for the formation of compound 1.
HN
C2H5O
Solvent / Tempreture
COOEt
Entry
O
O
O Catalyst
Catalyst
Time
Yield
(Mol)
(h)
( %)
– 0.04 0.04 0.04 0.04 0.04 0.04 0.04 0.04 0.04 0.02 0.08
36 16 17 17 18 15 15 16 15 11 12 11
Fig. 1 Biologically active molecules with 2-furanone as core skeleton.
3-Amino-2(5H)furanones
3,4-Diaryl-2(5H)-furanones
CHO
COOEt
NHR1
R2
0 55 53 52 54 65 62 61 70 85 75 60
Table 2 The effect of reusability of SSA catalyst on the furanone yield. Number of uses
Time (h)
Yield ( %)
Recovery of SSA ( %)
1 2 3 4
11 12 13 14
85 84 82 82
96 94 92 90
no reaction was occurred even at prolonged reaction time. In order to optimize the reaction conditions, aniline, DEACD and ▶ Fig. 2) 4-fluorobenzaldehyde were taken as model reactants. ( ● The preliminary trial was investigated for the reaction conditions with regard to different catalysts and solvents. The reaction was carried out using various catalysts (namely PPA/SiO2, SiCl4, HClO4SiO2, (CH3)3SiCl and SSA) in order to obtain the best catalyst (as shown in ● ▶ Table 1). From the obtained results, it was found that, the best catalyst in terms of yield and time was silica sulfuric acid (entry 6). The attention was then focused toward the effect of solvents on the yield of the one-pot assembly of the model. Replacing CH3OH by CH3CN or CH2Cl2 (entry 7, 8) produced the model in an appreciable yield lower than that of the one produced by the former (entry 6). Replacing CH3OH by ethanol (entry 9) produced the model in a yield higher than that of the one produced by the former (entry 6). For more investigation for the optimum condition for this reaction, we study the effect of temperature. A preliminary examination showed that when reaction temperature was 85 °C, it gave the best result (entry 10). Moreover, we study the efficacy of the ratio of the Basyouni WM et al. Furanones as Cytotoxic Agents … Drug Res 2015; 65: 473–478
O
O
catalyst (0.02, 0.04, 0.08 mol) and our study revealed that 0.04 mol of the catalyst was the optimum ratio (entry 10). From the obtained results, it was found that, the best catalyst was silica sulfuric acid (0.04 Mol). Optimized condition was established in EtOH as a solvent system using a reaction temperature at ▶ Table 1, entry 10); this remarkable activation in reac85 °C. ( ● tion rate prompted us to explore the potential of this protocol for the synthesis of other furan-2(5H)-ones. Reusability of the catalyst is an important factor from economical and environmental point of views and attracted much more attention in recent years. Therefore, the reusability of silica sulfuric acid was examined under optimized reaction conditions. The catalyst silica sulfuric acid is a super solid acid. Hence it is more convenient and cost effective catalyst. It exists in solid state and easily separated from reaction mixture simply by filtration. The catalyst was washed with ethyl acetate and diethyl ether and a fresh reaction was then performed under the same condition; SSA could be used for at least 4 times without signifi▶ Table 2). cant loss in product yield (85–82 %) ( ● To expand the scope of this novel methodology, aliphatic amines and several diversely substituted anilines having electrondonating as well as electron-withdrawing groups were reacted with 4-fluorobezaldehyde and DEACD in the presence of SSA. The reactions were finished at specified time and afford ethyl 2-(4-fluorophenyl)-4-(substituted amino)-5-oxo-2,5-dihydrofuran-3-carboxylates 1–10 in good yields (72–90 %) as shown ▶ Table 3. From the obtained results it was found in ● ▶ Fig. 2 and ● that aromatic amines bearing electron-donating group (compound 3) resulted the higher yield of the product (90 %) with reducing the time of reaction compared to amines with electron-withdrawing group (compound 6; 80 %). In order to generality of the above reaction, 4-fluorobezaldehyde was replaced by 3-bromobenzaldehyde in the model of the one-pot reaction. When 3-bromobenzaldehyde was left to react with various amines and DEACD in the presence of SSA, the reaction was finished at specified time and afforded the ethyl 2-(3-bromophenyl)4-(substituted amino)-5-oxo-2,5-dihydrofuran-3-carboxylates 11–14 in good yields (72–85 %). Also, it was observed that aromatic amines bearing electron-donating group (compound 12, 80 %) resulted in higher yields of the products compared to amines with electron-withdrawing groups (compound 14, 76 %). Moreover, our investigation was extended to include the behavior of heterocyclic aldehyde towards this reaction. Thus, when 2-thiophene aldehyde (as heterocyclic aldehyde) was reacted with DEACD and benzyl amine under similar conditions, the
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Br
Original Article 475 H-2 proton for the 2(5H)-furanone moieties as singlets around δ = 4.95–6.22 ppm region. The spectra revealed also the characteristic signals of carboethoxy groups as triplets around δ = 0.98–1.06 ppm and quartets around δ = 3.90–3.99 ppm, respectively. The multiplets of aromatic protons were appeared around δ = 6.78–8.57 ppm and the secondary amine protons (NH) on C3-furanone appeared as broad singlets around δ = 11.57–11.97 ppm (D2O-exchangeable). Moreover, 13C-NMR spectra were characterized by the presence of peaks corresponding to the 2 carbonyls at: around δ = 162.61 and 164.66 ppm. All other signals were in good agreement with the assigned structures. Aim of the present investigation was for synthesizing a series of 3,4,5-trisubstituted 2(5H)-furanone derivatives which bearing a
present reaction works well to afford ethyl 4-(benzylamino)5-oxo-2-(thiophen-2-yl)-2,5-dihydrofuran-3-carboxylate (16). Noteworthy to observe that, upon reacting 5-methylfuran2-carbaldehyde with DEACD and aniline or 4-flouroaniline under the same reaction conditions, there is no reaction occurred, this may be attributed to the acid sensitivity of the aldehyde (2-furfuraldehyde). The experimental results are ▶ Table 3. included in ● ▶ Fig. 3, ● Structure of the synthesized products 1–16 was established on the basis of their spectral data and elemental analyses. Thus, IR spectra exhibited the absorption bands around 1 721, 1 687 cm − 1, corresponding to 2C = O and around 3 302 cm − 1 corresponding to NH groups. The mass spectra of the products showed their respective [M + ] peaks. Moreover, their 1H NMR spectra revealed
Table 3 Reaction times, yields and cytotoxic activity of ethyl 2-(aryl)-4-(substitutedamino)-5-oxo- 2,5-dihydrofuran-3-carboxylate derivatives.
NHAr'
C2H5O Ar Compd. No. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 Doxorubicin
Ar
Ar’
C6H4F-4 C6H4F-4 C6H4F-4 C6H4F-4 C6H4F-4 C6H4F-4 C6H4F-4 C6H4F-4 C6H4F-4 C6H4F-4 C6H4Br-3 C6H4Br-3 C6H4Br-3 C6H4Br-3 C6H4Br-3 2-thienlyl
Time
C6H5 C6H4(CH3)-4 C6H4(OC2H5)-4 C6H4F-4 C6H4Cl-4 C6H4Br-4 C6H4(NO2)-3 n-C4H9 CH2Ph 2-thiazolyl C6H5 C6H4Cl-4 C6H4Br-4 C6H4(NO2)-3 n-C4H9 CH2Ph
Yield
11 10 10 14 15 16 17 17 17 15 14 15 15 16 16 15
IC50 µM of Cytotoxicity
85 89 90 82 81 80 78 73 74 72 85 80 79 76 72 65 0.007
O
COOEt Ar'NH2
ArCHO
O
O
COOEt
SSA/EtOH 85 °C
HN Ar'
C2H5O Ar
O
HepG2
MCF-7
CACO
0.002 0.019 0.002 0.201 0.227 0.210 0.208 0.212 0.188 0.212 0.168 0.149 0.158 0.169 0.227 – 0.005
0.002 0.020 0.019 0.205 0.237 0.229 0.208 0.030 0.201 0.218 0.188 0.182 0.141 0.170 0.249 – 0.004
> 0.3 > 0.3 > 0.3 > 0.3 > 0.3 > 0.3 > 0.3 > 0.3 > 0.3 > 0.3 > 0.3 > 0.3 > 0.3 > 0.3 > 0.3 –
Fig. 3 Synthesis of ethyl 2-(aryl)-4-(subamino)-5oxo- 2,5-dihydrofuran-3-carboxylate derivatives.
O
1-16 1 Ar = C 6 H4F-4 2 Ar = C 6 H4F-4 3 Ar = C 6 H4F-4 4 Ar = C 6 H4F-4 5 Ar = C 6 H4F-4 6 Ar = C 6 H4F-4 7 Ar = C 6 H4F-4 8 Ar = C 6 H4F-4
Ar' = C 6H5 Ar' = C 6H4(CH3)-4 Ar' = C 6H4(OC 2H5)-4 Ar' = C 6H4F-4 Ar' = C 6H4Cl-4 Ar' = C 6H4Br-4 Ar' = C 6H4(NO2)-3 Ar' = n-C 4H9
9 Ar = C 6H4 F-4 1 0 Ar = C 6H4 F-4 11 Ar = C 6H4Br-3 12 Ar = C 6H4Br-3 13 Ar = C 6H4Br-3 14 Ar = C 6H4Br-3 15 Ar = C 6H4Br-3 1 6 Ar = 2-thienyl
Ar' = CH2C 6 H5 Ar' = 2-thaiazolyl Ar' = C6H5 Ar' = C 6H4C l-4 Ar' = C6H4Br-4 Ar' = C6H4(NO 2)-3 Ar' = n-C4H9 Ar' = CH2C 6H5
Basyouni WM et al. Furanones as Cytotoxic Agents … Drug Res 2015; 65: 473–478
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O
476 Original Article
Basyouni WM et al. Furanones as Cytotoxic Agents … Drug Res 2015; 65: 473–478
The presence of thiazole nucleus does not improve the cytotoxic activity and showed slight activity against HEPG2 and MCF7 cell lines (IC50 about 0.21 µM). For instance, compounds 11–15, Ar was 3-bromophenyl moiety and Ar' were Ph; 11, C6H4Cl-4; 12, C6H4Br-4; 13, C6H4(NO2)-3; 14, n-C4H9; 15. In general, the mean values of IC50 obtained for these compounds suggest that: replacement of 4-fluorophenyl moiety by 3-bromophenyl moiety proved to be detrimental to cytotoxic activity. Introduction of bromophenyl moiety showed slight activity against HEPG2 and MCF7 cell lines (IC50 0.14– 0.24 µM).
Experimental Section
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All melting points were determined on an electrothermal Gallenkamp apparatus and are uncorrected. Analytical TLC was performed with silica gel GF254 plates, and the products were visualized by UV detection. 1H, 13C and NMR spectra were recorded on a Bruker AVANVE 600 NMR spectrometer {1H 600.13 MHz; 13C 150.91 MHz equipped with TBI probe head. Samples were measured in DMSO-d6 1H NMR (500 MHz) spectra were recorded in DMSO-d6. Chemical shifts (δ) are reported in ppm using TMS as internal standard and spin-spin coupling constants (J) are given in Hz. The mass spectra (EI) spectra were measured on an HP 5988A spectrometer by direct inlet at 70 eV. Elemental analyses were carried out by the Micro-analytical Laboratory, National Research Centre, Cairo, Egypt.
General procedure for synthesis of 3, 4, 5-substituted furan-2(5H)-one derivatives
A mixture of aldehyde (2.0 mmol), amine (2.0 mmol), diethylacetylene-dicarboxylate (2.0 mmol), and SSA (0.11 g) was dissolved in EtOH (5 mL) after which the reaction mixture was heated at 85 °C until completion of the reaction as indicated by TLC. Upon and on completion, CH2Cl2 was added and catalyst was removed by filtration. Filtrates were washed with saturated NaHCO3 (aq) and brine, dried with anhydrous Na2SO4, and concentrated to dryness. Finally, the residue was purified by silica gel chromatographic methods to obtain the following pure product.
Ethyl 2-(4-fluorophenyl)-5-oxo-4-(phenylamino)-2,5-dihydrofuran-3-carboxylate (1): pale yellow solid; mp = 179–181 °C; Rf = 0.17 (28 % ethyl acetate in petroleum ether); IR: ν/cm − 1: 3 295 (NH), 1 718, 1 664 (C = O); 1H NMR: δ/ppm = 1.04 (t, J = 6.90 Hz, 3H, CH2CH3), 3.97 (q, J = 6.90 Hz, 2H, CH2), 6.02 (s, 1H, CH furanone), 6.99–7.51 (m, 8H, ArH), 11.79 (br, 1H, NH); MS (m/z, %): 341 (M + , 100); Anal. Calcd. for C19H16FNO4 (341.11): C, 66.86; H, 4.72; N, 4.10; Found: C, 66.58; H, 4.97; N, 4.22. Ethyl 2-(4-fluorophenyl)-5-oxo-4-(p-tolylamino)-2,5-dihydrofuran-3-carboxylate (2): pale yellow solid; mp = 177–179 °C; Rf = 0.60 (33 % ethyl acetate in petroleum ether); IR: ν/cm − 1: 3 307 (NH), 1 727, 1 688 (C = O); 1H NMR: δ/ppm = 1.04 (t, J = 6.85 Hz, 3H, CH2CH3), 2.21 (s, 3H, CH3), 3.98 (q, J = 6.85 Hz, 2H, CH2), 6.00 (s, 1H, CH furanone), 6.99–7.39 (m, 8H, ArH), 11.67 (br, 1H, NH); MS (m/z, %): 355 (M + , 100); Anal. Calcd. for C20H18FNO4 (355.12): C, 67.60; H, 5.11; N, 3.94; Found: C, 67.30; H, 5.25; N, 3.80.
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4-flourophenyl (or 3-bromophenyl) at position-5 and various substituents at position-3. The cytotoxic activity of the synthesized compounds was evaluated against human hepatocellular carcinoma cell line (HEPG2), human breast cancer cell line (MCF7) and human colon adenocarcinoma cell line (CACO). Doxorubicin (CAS-23214–92–8) was used as a reference drug, which considers one of the most effective anticancer agent. Potential cytotoxicity of the compounds was tested using the method of ▶ Table 3. Using Skehan et al. [16]. IC50 value was summarized in ● the general structure provided in ● ▶ Table 3, certain aspects of the structure activity relationships for these compounds can be more clearly highlighted. As anticipated, a clear difference in cytotoxic activity was noted between compounds under investigation. The mean values of IC50 represented that: all tested compounds possessed IC50 > 0.3 µM against the growth of CACO, but some tested compounds possessed significant cytotoxic activity against the growth of HEPG2 and MCF7. For instance, compounds 1–10, where Ar was 4-flourophenyl moiety and Ar' were Ph; 1, C6H4(CH3)-4; 2, C6H4(OC2H5)-4; 3, C6H4F-4; 4, C6H4Cl-4; 5, C6H4Br-4; 6, C6H4(NO2)-3; 7, n-C4H9; 8, CH2Ph; 9, 2-thiazolyl; 10. Regarding the effect of Ar' group, it was evident that varying such a unit may have a dramatic effect on cytotoxic activity, which may be augmented or reduced depending on whether a matching or mismatching relationship exists with the Ar 'group. The type of the substitution on the benzene ring of Ar' moiety is important. It was noticed that the presence of electron donating group at the benzene ring or leaving benzene ring without substitution had a potent effect on cytotoxic activity. The presence of unsubstituted benzene ring (1) resulted in the highest cytotoxic activity among all the compounds investigated in this study. The presence of unsubstituted benzene moiety was exhibited significant antitumor activity against HEPG2 and MCF7 cell lines (IC50 values 0.002 and 0.002 µM, respectively) more than reference drug (IC50 0.007, 0.005 µM). Compound 3 with 4-ethoxyphenyl moiety showed significant antitumor activity (IC50 0.002 µM) more than reference drug (0.007 µM) against HEPG2 cell line and exhibited a good activity against MCF7 cell line (IC50 0.019 µM). Also, compound 2 (4-methylphenyl moiety) showed good activity against HEPG2 and MCF7 cell lines. The presence of electron withdrawing halogen-atom such as Cl and Br at the benzene ring had a detrimental effect on cytotoxic activity. Introduction of bromophenyl moiety in case of compound 6 resulted in the lowest cytotoxic activity among all the compounds investigated in this study. 4-Chlorophenyl, 5; 4-bromophenyl, 6 showed slight activity against MCF7 and HEPG2 cell lines (IC50 about 0.21 µM). The presence of 4-fluorophenyl moiety showed IC50 about 0.2 µM against HEPG2 and MCF7. Introduction of polar group such as nitro group at the benzene ring in case of compound 7 had a detrimental effect on cytotoxic activity. Compound 7 showed slight activity against MCF7 and HEPG2 cell lines (IC50 about 0.2 µM). When Ar' was replaced by alkyl moiety, such as n-butyl moiety in case of compound 8 a moderate activity against MCF7 cell line (IC50 0.03 µM) was observed with a slight activity against HEPG2 cell line (IC50 0.21 µM). The presence of CH2Ph moiety (compound 9) reflect a slight activity against HEPG2 and MCF7 cell lines (IC50 0.18 and 0.20 µM, respectively).
Original Article 477
Ethyl 2-(4-fluorophenyl)-4-(4-fluorophenylamino)-5-oxo-2,5dihydrofuran-3-carboxylate (4): white solid; mp = 153–155 °C. Rf = 0.26 (28 % ethyl acetate in petroleum ether); IR: ν/cm − 1: 3 299 (NH), 1 727, 1 690(C = O) cm − 1; 1H NMR: δ/ppm = 1.04 (t, J = 6.85Hz, 3H, CH2CH3), 3.99 (q, J = 6.85 Hz 2H, OCH2), 6.05 (s, 1H, CH furanone), 7.02–7. 59 (m, 8H, ArH), 11.78 (b, 1H, NH) ppm; MS (m/z, %): 359 (M + , 100); Anal. Calcd. for C19H15F2NO4 (359.10): C, 63.51; H, 4.21; N, 3.90; Found: C, 63.51; H, 4.21; N, 3.90. Ethyl 4-(4-chlorophenylamino)-2-(4-fluorophenyl)-5-oxo-2,5dihydrofuran-3-carboxylate (5): pale yellow solid; mp = 172– 174 °C. Rf = 0.48 (28 % ethyl acetate in petroleum ether); IR: ν/ cm − 1: 3 304 (NH), 1 730, 1 685 (C = O); 1H NMR: δ/ppm = 1.05 (t, J = 6.87Hz, 3H, CH2CH3), 3.98 (q, J = 6.87 Hz 2H, OCH2), 6.07 (s, 1H, CH furanone), 7.01–7.58 (m, 8H, ArH), 11.79 (br, 1H, NH); MS (m/z, %): 375 (M + , 76.29). Anal. Calcd. for C19H15ClFNO4 (375.07): C, 60.73; H, 4.02; N, 3.73; Found: C, 60.66; H, 4.12; N, 3.82. Ethyl 4-(4-bromophenylamino)-2-(4-fluorophenyl)-5-oxo-2,5- dihydrofuran-3-carboxylate (6): pale yellow solid; mp = 180– 182 °C; Rf = 0.68 (33 % ethyl acetate in petroleum ether); IR: ν/ cm − 1: 3 304 (NH), 1 731, 1 687 (C = O); 1H NMR: δ/ppm = 1.04 (t, J = 6.87Hz, 3H, CH2CH3), 3.98 (q, J = 6.87 Hz 2H, OCH2), 6.13 (s, 1H, CH furanone), 7.01–7.52 (m, 8H, ArH), 11.80 ( br, 1H, NH); MS (m/z, %): 419 (M + , 18.63); Anal. Calcd. for C19H15BrFNO4 (419.02): C, 54.30; H, 3.60; N, 3.33; Found: C, 54.47; H, 3.54; N, 3.22. Ethyl 2-(4-fluorophenyl)-4-(3-nitrophenylamino)-5-oxo-2,5- dihydrofuran-3-carboxylate (7): white solid; mp = 227–229 °C; Rf = 0.13 (33 % ethyl acetate in petroleum ether); IR: ν/cm − 1: 3 302 (NH), 1 721, 1 687 (C = O); 1H NMR: δ/ppm = 1.06 (t, J = 6.87 Hz, 3H, CH2CH3), 3.99 (q, J = 6.87 Hz 2H, CH2), 6.22 (s, 1H, CH furanone), 7.02–8.57 (m, 8H, ArH), 11.97 (br, 1H, NH); 13C NMR: 13.9 (CH3), 59.7 (CH -furanone), 59.8 (CH2), 112.5, 115.1, 115.3, 116.4, 119.7, 127.9, 129.9, 130.0, 130.1, 132.1, 137.2, 147.8, 152.2, 160.4, 161.8 (C = O), 164.3 (C = O); MS (m/z, %): 386 (M + , 17.20); Anal. Calcd. for C19H15FN2O6 (386.09): C, 59.07; H, 3.91; N, 7.25; Found: C, 59.14; H, 3.85; N, 7.19. Ethyl 4-(butylamino)-2-(4-fluorophenyl)-5-oxo-2,5-dihydrofuran-3-carboxylate (8): white solid; mp = 202–204 °C; Rf = 0.33 (28 % ethyl acetate in petroleum ether); IR: ν/cm − 1: 3 132 (NH), 1 681 (C = O) cm − 1; 1H NMR: δ/ppm = 0.76 ( t, J = 7.27 Hz, 3H, N-CH2CH2CH2CH3), 1.00 (t, J = 7.25 Hz, 3H, CH2CH3), 1.11 (m, 3H, N-CH2CH2CH2CH3), 1.32 (m, 3H, N-CH2CH2CH2CH3), 2.54 (m, 1H, N-CH.), 3.47 (m, 1H, N-CH), 3.96 (q, J = 7.25 Hz, 2H, OCH2), 5.20 (s, 1H, CH furanone), 7.13–7.21 (m, 4H, ArH), 11.57 (br, 1H, NH); 13 C NMR: 13.6 (CH3), 13.9 (CH3), 19.8 (CH2), 30.2 (CH2), 40.0 (CH2), 59.7 (CH-furanone), 61.0 (CH2), 112.6, 114.5, 115.7, 115.8, 129.4, 130.6, 157.6, 163.4 (C = O), 165.0 (C = O); MS (m/z, %): 321
(M + , 2.89); Anal. Calcd. for C17H20FNO4 (321.14): C, 63.54; H, 6.27; N, 4.36; Found: C, 63.49; H, 6.33; N, 4.29.
Ethyl 4-(benzylamino)-2-(4-fluorophenyl)-5-oxo-2,5-dihydrofuran-3-carboxylate (9): white solid; mp = 202–204 °C. Rf = 0.44 (33 % ethyl acetate in petroleum ether); IR: ν/cm − 1: 3 158 (NH), 1 678 (C = O); 1H NMR: δ/ppm = 0.98 (t, J = 6.85 Hz, 3H, CH2CH3), 3.67 (d, J = 15.3 Hz, 1H, N-CH), 3.95 (q, J = 6.85 Hz, 2H, CH2), 4.76 (d, J = 15.3 Hz, 1H, N-CH), 4.95 (s, 1H, CH furanone), 7.02–7.24 (m, 9H, ArH), 11.79 (br, 1H, NH); MS (m/z, %): 355 (M + , 0.32); Anal. Calcd. for C20H18FNO4 (355.12): C, 67.60; H, 5.11; N, 3.94; Found: C, 67.45; H, 5.35; N, 3.72 Ethyl 2-(4-fluorophenyl)-5-oxo-4-(thiazol-2-ylamino)-2,5-di hydrofuran-3-carboxylate (10): pale yellow solid; mp = 170– 172 °C. Rf = 0.55 (28 % ethyl acetate in petroleum ether); IR (KBr) υ: 3 171 (NH), 1 728,1 633 (C = O) cm − 1; 1H NMR: δ/ppm = 1.05 (t, J = 6.90 Hz, 3H, CH2CH3), 3.95 (q, J = 6.90 Hz 2H, OCH2), 6.09(s, 1H, CH furanone), 7.32–8.28 (m, 6H, ArH), 11.94 (b, 1H, NH); MS (m/z, %): 348(M + , 21.80); Anal. Calcd. for C16H13FN2O4S (348.06): C, 55.17; H, 3.76; N, 8.04 Found: C, 55.25; H, 3.61; N, 8.17 %. Ethyl 2-(3-bromophenyl)-5-oxo-4-(phenylamino)-2,5-dihydrofuran-3-carboxylate (11): pale yellow solid; mp = 187–189 °C; Rf = 0.37 (28 % ethyl acetate in petroleum ether); IR (KBr) υ: 3 302 (NH), 1 722,1 651 (C = O) cm − 1; 1H NMR: δ/ppm = 1.05 (t, J = 6.87 Hz, 3H, CH2CH3), 3.94 (q, J = 6.87 Hz, 2H, OCH2), 6.09 (s, 1H, CH furanone), 6.95–7.52 (m, 8H, ArH), 11.92 (b, 1H, NH) ppm; 13C NMR (150 MHz, DMSO) δ = 13.89 (CH3), 60.75 (CHfuranone), 61.41 (CH2), 112.72 (C), 122.12 (CH), 122.41 (C), 125.85 (CH), 126.03 (CH), 126.05 (CH), 129.10 (CH), 130.19 (CH), 130.76 (CH), 131.67 (CH), 135.91 (C), 137.49 (C), 156.66 (C), 162.65 (C = O), 164.89 (C = O); MS (m/z, %): 402(M + , 88.58); Anal. Calcd. for C19H16BrNO4 (401.03): C, 56.73; H, 4.01; N, 3.48 Found: C, 56.65; H, 4.11; N, 3.28 %. Ethyl 2-(3-bromophenyl)-4-(4-chlorophenylamino)-5-oxo-2,5dihydrofuran-3-carboxylate (12): pale yellow solid; mp = 178– 180 °C; Rf = 0.68 (33 % ethyl acetate in petroleum ether); IR: ν/ cm − 1: 3 307 (NH), 1 725, 1 691 (C = O); 1H NMR: δ/ppm = 1.06 (t, J = 6.87 Hz, 3H, CH2CH3), 4.02 (q, J = 6.87 Hz, 2H, CH2), 6.07 (s, 1H, CH furanone), 7.19–7.60 (m, 8H, ArH), 11.89 (br, 1H, NH); 13C NMR: 13.8 (CH3), 60.6 (CH-furanone), 61.4 (CH2), 112.8, 122.4, 122.9, 125.7, 129.1, 130.2, 130.6, 131.2, 131.7, 134.4, 137.1, 156.1, 162.6 (C = O), 164.6 (C = O); MS (m/z, %): 437 (M + H + 95.58); Anal. Calcd. for C19H15BrClNO4 (434.99): C, 52.26; H, 3.46; N, 3.21; Found: C, 52.35; H, 3.28 N, 3.32. Ethyl 2-(3-bromophenyl)-4-(4-bromophenylamino)-5-oxo-2, 5-dihydrofuran-3-carboxylate (13): white solid; mp = 189– 191 °C; Rf = 0.63 (33 % ethyl acetate in petroleum ether); IR (KBr) υ: 3 306 (NH), 1 725,1 663 (C = O) cm − 1; 1H NMR: δ/ppm = 1.06 (t, J = 6.85 Hz, 3H, CH2CH3), 4.02 (q, J = 6.85 Hz 2H, OCH2), 6.07(s, 1H, CH furanone), 7.46–7.54 (m, 8H, ArH), 11.88 (brs, 1H, NH); MS (m/z, %): 481.85(M + , 17.33); Anal. Calcd. for C19H15Br2NO4 (478.94): C, 47.43; H, 3.14; N, 2.91 Found: C, 47.26; H, 3.35; N, 2.79 %. Ethyl 2-(3-bromophenyl)-4-(3-nitrophenylamino)-5-oxo-2,5- dihydrofuran-3-carboxylate (14): white solid; mp = 196–198 °C; Rf = 0.44 (33 % ethyl acetate in petroleum ether); IR: ν/cm − 1: 3 320 (NH), 1 727, 1 684 (C = O) cm − 1; 1H NMR: δ/ppm = 1.07 (t, Basyouni WM et al. Furanones as Cytotoxic Agents … Drug Res 2015; 65: 473–478
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Ethyl 4-(4-ethoxyphenylamino)-2-(4-fluorophenyl)-5-oxo-2, 5-dihydrofuran-3-carboxylate (3): white solid; mp = 156–158 °C; Rf = 0.28 (28 % ethyl acetate in petroleum ether); IR: ν/cm − 1: 3 321 (NH), 1 717, 1 682 (C = O); 1H NMR: δ/ppm = 1.04 (t, J = 6.90 Hz, 3H, CH2CH3), 1.23 (t, J = 6.90 Hz, 3H, CH2CH3), 3.90 (q, J = 6.90 Hz 2H, CH2),, 3.96 (q, J = 6.90 Hz, 2H, OCH2), 5.96 (s, 1H, CH furanone), 6.78–7.37 (m, 8H, ArH), 11.69 (s, 1H, NH); MS (m/z, %): 385 (M + , 66.8); Anal. Calcd. for C21H20FNO5 (385.13): C, 65.45; H, 5.23; N, 3.63; Found: C, 65.50; H, 5.15; N, 3.60
478 Original Article
Ethyl 2-(3-bromophenyl)-4-(butylamino)-5-oxo-2,5-dihydrofuran-3-carboxylate (15): white solid; mp = 202–204 °C; Rf = 0.11 (28 % ethyl acetate in petroleum ether); IR: ν/cm − 1: 3 150 (NH), 1 680 (C = O) cm − 1; 1H NMR: δ/ppm = 0.76 (t, J = 7.25 Hz, 3H, N-CH2CH2CH2CH3), 1.01 (t, J = 7.25 Hz, 3H, CH2CH3), 1.03 (m, 3H, N-CH2CH2CH2CH3), 1.25 (m, 3H, N-CH2CH2CH2CH3), 2.55 (m, 1H, N-CH), 3.48 (m, 1H, N-CH), 3.92 (m, 1H, CH), 3.99 (m, 1H, CH), 5.21 (s, 1H, CH furanone), 7.15–7.47 (m, 4H, ArH), 11.69 (br, 1H, NH); MS (m/z, %): 381 (M + , 18.50); Anal. Calcd. for C17H20BrNO4 (381.06): C, 53.42; H, 5.27; N, 3.66; Found: C, 53.35; H, 5.21; N, 3.59 %. Ethyl 4-(benzylamino)-5-oxo-2-(thiophen-2-yl)-2,5-dihydrofuran-3-carboxylate (16): white solid; mp = 160–162 °C. Rf = 0.28 (33 % ethyl acetate in petroleum ether); IR: ν/cm − 1: 3 145 (NH), 1 681 (C = O) cm − 1; 1H NMR: δ/ppm = 1.01 (t, J = 6.87 Hz, 3H, CH2CH3), 3.79 (d, J = 15.25 Hz, 1H, N-CH), 3.99 (q, J = 6.87 Hz, 2H, OCH2), 4.80 (d, J = 15.30 Hz, 1H, N-CH), 5.29 (s, 1H, CH furanone), 7.07–7.28 (m, 8H, ArH), 11.85 (br, 1H, NH); MS (m/z, %): 343 (M + , 92.50); Anal. Calcd. for C18H17NO4S (343.09): C, 62.96; H, 4.99; N, 4.08; Found: C, 62.80; H, 4.66; N, 4.26.
Conflict of Interest
▼
The authors have no conflict of interest to disclose.
Basyouni WM et al. Furanones as Cytotoxic Agents … Drug Res 2015; 65: 473–478
References
1 Bailly F, Queffelec C, Mbemba G et al. Synthesis and biological activities of a series of 4,5-diaryl-3-hydroxy-2(5H)-furanones. Eur J Med Chem 2008; 43: 1222–1229 2 Borate HB, Sawargave SP, Chavan SP et al. Novel hybrids of fluconazole and furanones: Design, synthesis and antifungal activity. Bioorg Med Chem Lett 2011; 21: 4873–4878 3 March P, Font J, Gracia A et al. Easy Access to 5-Alkyl-4-bromo-2(5H)furanones: Synthesis of a Fimbrolide, an Acetoxyfimbrolide, and Bromobeckerelide. J Org Chem 1995; 60: 1814–1822 4 Raic-Malic S, Svedruzic D, Gazivoda T et al. Synthesis and Antitumor Activities of Novel Pyrimidine Derivatives of 2,3-O,O-Dibenzyl-6-deoxy-l-ascorbic Acid and 4,5-Didehydro-5,6- dideoxy-l-ascorbic Acid. J Med Chem 2000; 43: 4806–4811 5 Bellina F, Anselmi C, Martina F et al. Mucochloric Acid: A Useful Synthon for the Selective Synthesis of 4-Aryl-3-chloro-2(5H)-furanones, (Z)-4Aryl-5-1-(aryl)methylidene]-3-chloro-2(5H)-furanones and 3,4-Diaryl2(5H)-furanones. Eur J Org Chem 2003; 2003: 2290–2302 6 Kim Y, Nam N-H, You Y-J et al. Synthesis and Cytotoxicity of 3,4-Diaryl2(5H)-furanones. Bioorg Med Chem Lett 2002; 12: 719–722 7 Iannazzo D, Piperno A, Romeo G et al. Synthesis and Cytotoxicity of 3,4-Diaryl-2(5H)-furanones. Bioorg Med Chem 2008; 16: 9610–9615 8 Cao R, Liu C, Liu L. A convenient synthesis of 2(5H)-furanone. Org Prep Proced Int 1996; 28: 215–216 9 Fu C, Ma S. Efficient Preparation of 4-Iodofuran-2(5H)-ones by Iodolactonisation of 2,3-Allenoates with I2. Eur J Org Chem 2005; 2005: 3942–3945 10 Mabon R, Richecoeur AME, Sweeney JB. Preparation and reactions of 3,4-bisstannyl-2(5H)furanones. Tetrahedron 2002; 58: 9117–9129 11 Bellina F, Falchi E, Rossi R. Regioselective synthesis of cytotoxic 4-(1-alkynyl)-substituted 2-(5H)-furanones. Tetrahedron 2003; 59: 9091–9100 12 Abbas SY, El-Sharief MAMSh, Basyouni WM et al. Thiourea derivatives incorporating a hippuric acid moiety: Synthesis and evaluation of antibacterial and antifungal activities. Eur J Med Chem 2013; 64: 111–120 13 Aly MM, Mohamed YA, El-Bayouki KhAM et al. Synthesis and biological activity of some 4(3H)-quinazolinone-2-carboxaldehyde thiosemicarbazone and their metal complexes. Eur J Med Chem 2010; 45: 3365–3373 14 El-Sharief MAMSh, Abbas SY, El-Bayouki KAM et al. Synthesis of thiosemicarbazones derived from N-(4-hippuric acid) thiosemicarbazide and different carbonyl compounds as antimicrobial agents. Eur J Med Chem 2013; 67: 263–268 15 El-Bayouki KhAM, Basyouni WM, Mostafa EA et al. Synthesis, characterization and molluscicidal activity of Mn, Co, Ni and Cu metal complexes of ethyl 5-amino-2-(methylthio) thiazole-4-carboxylate. Synth React Inorg Met-Org 2014; 44: 537–540 16 Skehan P, Storeng R, Scudiero D et al. New Colorimetric Cytotoxicity Assay for Anticancer-Drug Screening. JNCI J Natl Cancer Inst 1990; 82: 1107–1112
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J = 6.87 Hz, 3H, CH2CH3), 3.99 (q, J = 6.87 Hz 2H, CH2), 6.21 (s, 1H, CH furanone), 7.15–8.60 (m, 8H, ArH), 12.06 (br, 1H, NH); MS (m/z, %): 447 (M + , 8.49); Anal. Calcd. for C19H15BrN2O6 (446.01): C, 51.03; H, 3.38; N, 6.26; Found: C, 51.09; H, 3.31; N, 6.20.
3,4,5-Trisubstituted Furan-2(5H)-one Derivatives: Efficient one-pot Synthesis and Evaluation of Cytotoxic Activity
Authors
W. M. Basyouni1, Kh. A. M. El-Bayouki1, A. S. El-Sayed2, W. M. Tohamy1, M. M. S. Farag3, M. A. Abd-El-Baseer4
Affiliations
1
Key words ▶ one-pot synthesis ● ▶ furan-2(5H)-one ● ▶ silica sulfuric acid ● ▶ cytotoxicity ●
Abstract
Organometallic and Organometalloid Chemistry Department, National Research Centre, Cairo, Egypt Chemistry Department, Faculty of Science, Al-Azhar University, Cairo, Egypt 3 Botany and Microbiology Department, Faculty of Science, Al-Azhar University, Cairo, Egypt 4 Center for Virus Research and Studies, Al-Azhar University, Cairo, Egypt
▼
A series of 3,4,5-trisubstituted 2(5H)-furanone derivatives was synthesized through one-pot reaction of amines, aldehydes and diethyl acetylenedicarboxylate. Silica sulfuric acid efficiently catalyzes the 3-component reaction to afford the corresponding 2(5H)-furanones in high yields. The synthesized compounds were tested against
Introduction
▼
received 24.03.2014 accepted 04.08.2014 Bibliography DOI http://dx.doi.org/ 10.1055/s-0034-1387768 Published online: September 10, 2014 Drug Res 2015; 65: 473–478 © Georg Thieme Verlag KG Stuttgart · New York ISSN 2194-9379 Correspondence W. M. Basyouni Organometallic and Organometalloid Chemistry Department National Research Centre Dokki Cairo 12622 Egypt Tel.: + 202/333/35 994 Fax: + 202/333/70 931 [email protected]
2-Furanone moiety has received considerable attention due to their significant biological activities such as antifungal agents [1, 2]. 2-Furanone moiety is frequently found as a substructure in natural products. The natural furanone such as fimbrolide [3] and their derivatives have possessed antiviral, antibiotic and anticancer activities [4]. Moreover, the synthetic 3,4-diaryl2(5H)-furanones have also been reported as cytotoxic agents [5, 6] and the 3-amino-2(5H) furanones able to block the replication of sub▶ Fig. 1). genomic RNA of HCV in liver cells [7] ( ● Synthesis of 2(5H)-furanone by heating furfural with hydrogen peroxide leading to a mixture of 2(3H)- and 2(5H)-furanones [8]. Chunling Fu et al. [9] developed the synthesis of 4-iodofuran-2(5H)ones from iodolactonisation of allenoates with molecular iodine. Preparation of 3,4-bistributylstannyl 2(5H)-furanones by reacting TBS as well as THP protected butynoate with hexabutylditin in the presence of PdCl2(PPh3)2 leading to substituted acrylate intermediate, which upon treating under a variety of conditions yielded the desired furanone synthon [10]. The 4-(1-alkynyl)-3-chloro (or bromo)-2(5H)-furanones [11] were synthesized by the Pd/Cu-catalyzed Sonogashira reaction involving treatment of 1-alkynes with 3,4-dichloro (or dibromo)-2(5H)-furanone, respectively, in the presence of KF as a base. The above mentioned methods suffer from certain limitations like multi-
HEPG2, MCF7 and CACO tumor cell lines. The cytotoxic activity for the tested compounds showed that: ethyl 2-(4-fluorophenyl)-5-oxo4-(phenylamino)-2,5-dihydrofuran-3-carboxylate exhibited significant antitumor activity against HEPG2 and MCF7 cell lines (IC50 values 0.002 and 0.002 µM, respectively) more than reference drug (IC50 0.007, 0.005 µM).
step strategies, low yields, use of costly metal catalysts and harsh condition. Due to the pharmacological importance, several protocols aimed to improve the synthesis of furan-2(5H)-ones have been reported. However, some of the newer reported methods also suffer from drawbacks such as unsatisfactory yields, cumbersome product isolation procedures and environmental pollution. Therefore, development of a new reagent with a wide range of structure diversity is needed. In view of the recent trends on the catalytic processes towards the development of clean and green chemical processes, investigation of new, less hazardous chemical catalysts has become a priority in synthesis of organic chemistry. As a part of our extensive research program to rapidly assemble novel bioactive compounds under mild conditions, [12–15], it was of interest to synthesize a novel series of 2(5H)-furanone in excellent yield through one-pot synthesis (multi-component reactions) in the presence of inexpensive silica sulfuric acid (SSA), and preliminary evaluation of the cytotoxic property of the synthesized compounds.
Results and Discussion
▼
In the initial study, when aniline let to react with diethyl acetylenedicarboxylate (DEACD) and 4-fluorobenzaldehyde in absolute ethanol without catalyst (entry 1), it was found that there is
Basyouni WM et al. Furanones as Cytotoxic Agents … Drug Res 2015; 65: 473–478
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2
474 Original Article
O
H2C
C4H9
Ar2
O
O
H 2C
Fimbrolide
NH2
O
O
Ar1
O
Protoanemonin
O
R3
F
F
Table 1 Results of compound 1 with different catalysts and solvents.
1 2 3 4 5 6 7 8 9 10 11 12
Catalyst
Solvent/T
None PPA/SiO2 SiCl4 HClO4SiO2 Me3SiCl SSA SSA SSA SSA SSA SSA SSA
EtOH/rt EtOH/rt CH2Cl2/rt EtOH/rt EtOH/rt MeOH/rt CH3CN/rt CH2Cl2 /rt EtOH/rt EtOH/85◦C EtOH/85◦C EtOH/85◦C
Fig. 2 Optimization of reaction conditions for the formation of compound 1.
HN
C2H5O
Solvent / Tempreture
COOEt
Entry
O
O
O Catalyst
Catalyst
Time
Yield
(Mol)
(h)
( %)
– 0.04 0.04 0.04 0.04 0.04 0.04 0.04 0.04 0.04 0.02 0.08
36 16 17 17 18 15 15 16 15 11 12 11
Fig. 1 Biologically active molecules with 2-furanone as core skeleton.
3-Amino-2(5H)furanones
3,4-Diaryl-2(5H)-furanones
CHO
COOEt
NHR1
R2
0 55 53 52 54 65 62 61 70 85 75 60
Table 2 The effect of reusability of SSA catalyst on the furanone yield. Number of uses
Time (h)
Yield ( %)
Recovery of SSA ( %)
1 2 3 4
11 12 13 14
85 84 82 82
96 94 92 90
no reaction was occurred even at prolonged reaction time. In order to optimize the reaction conditions, aniline, DEACD and ▶ Fig. 2) 4-fluorobenzaldehyde were taken as model reactants. ( ● The preliminary trial was investigated for the reaction conditions with regard to different catalysts and solvents. The reaction was carried out using various catalysts (namely PPA/SiO2, SiCl4, HClO4SiO2, (CH3)3SiCl and SSA) in order to obtain the best catalyst (as shown in ● ▶ Table 1). From the obtained results, it was found that, the best catalyst in terms of yield and time was silica sulfuric acid (entry 6). The attention was then focused toward the effect of solvents on the yield of the one-pot assembly of the model. Replacing CH3OH by CH3CN or CH2Cl2 (entry 7, 8) produced the model in an appreciable yield lower than that of the one produced by the former (entry 6). Replacing CH3OH by ethanol (entry 9) produced the model in a yield higher than that of the one produced by the former (entry 6). For more investigation for the optimum condition for this reaction, we study the effect of temperature. A preliminary examination showed that when reaction temperature was 85 °C, it gave the best result (entry 10). Moreover, we study the efficacy of the ratio of the Basyouni WM et al. Furanones as Cytotoxic Agents … Drug Res 2015; 65: 473–478
O
O
catalyst (0.02, 0.04, 0.08 mol) and our study revealed that 0.04 mol of the catalyst was the optimum ratio (entry 10). From the obtained results, it was found that, the best catalyst was silica sulfuric acid (0.04 Mol). Optimized condition was established in EtOH as a solvent system using a reaction temperature at ▶ Table 1, entry 10); this remarkable activation in reac85 °C. ( ● tion rate prompted us to explore the potential of this protocol for the synthesis of other furan-2(5H)-ones. Reusability of the catalyst is an important factor from economical and environmental point of views and attracted much more attention in recent years. Therefore, the reusability of silica sulfuric acid was examined under optimized reaction conditions. The catalyst silica sulfuric acid is a super solid acid. Hence it is more convenient and cost effective catalyst. It exists in solid state and easily separated from reaction mixture simply by filtration. The catalyst was washed with ethyl acetate and diethyl ether and a fresh reaction was then performed under the same condition; SSA could be used for at least 4 times without signifi▶ Table 2). cant loss in product yield (85–82 %) ( ● To expand the scope of this novel methodology, aliphatic amines and several diversely substituted anilines having electrondonating as well as electron-withdrawing groups were reacted with 4-fluorobezaldehyde and DEACD in the presence of SSA. The reactions were finished at specified time and afford ethyl 2-(4-fluorophenyl)-4-(substituted amino)-5-oxo-2,5-dihydrofuran-3-carboxylates 1–10 in good yields (72–90 %) as shown ▶ Table 3. From the obtained results it was found in ● ▶ Fig. 2 and ● that aromatic amines bearing electron-donating group (compound 3) resulted the higher yield of the product (90 %) with reducing the time of reaction compared to amines with electron-withdrawing group (compound 6; 80 %). In order to generality of the above reaction, 4-fluorobezaldehyde was replaced by 3-bromobenzaldehyde in the model of the one-pot reaction. When 3-bromobenzaldehyde was left to react with various amines and DEACD in the presence of SSA, the reaction was finished at specified time and afforded the ethyl 2-(3-bromophenyl)4-(substituted amino)-5-oxo-2,5-dihydrofuran-3-carboxylates 11–14 in good yields (72–85 %). Also, it was observed that aromatic amines bearing electron-donating group (compound 12, 80 %) resulted in higher yields of the products compared to amines with electron-withdrawing groups (compound 14, 76 %). Moreover, our investigation was extended to include the behavior of heterocyclic aldehyde towards this reaction. Thus, when 2-thiophene aldehyde (as heterocyclic aldehyde) was reacted with DEACD and benzyl amine under similar conditions, the
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Br
Original Article 475 H-2 proton for the 2(5H)-furanone moieties as singlets around δ = 4.95–6.22 ppm region. The spectra revealed also the characteristic signals of carboethoxy groups as triplets around δ = 0.98–1.06 ppm and quartets around δ = 3.90–3.99 ppm, respectively. The multiplets of aromatic protons were appeared around δ = 6.78–8.57 ppm and the secondary amine protons (NH) on C3-furanone appeared as broad singlets around δ = 11.57–11.97 ppm (D2O-exchangeable). Moreover, 13C-NMR spectra were characterized by the presence of peaks corresponding to the 2 carbonyls at: around δ = 162.61 and 164.66 ppm. All other signals were in good agreement with the assigned structures. Aim of the present investigation was for synthesizing a series of 3,4,5-trisubstituted 2(5H)-furanone derivatives which bearing a
present reaction works well to afford ethyl 4-(benzylamino)5-oxo-2-(thiophen-2-yl)-2,5-dihydrofuran-3-carboxylate (16). Noteworthy to observe that, upon reacting 5-methylfuran2-carbaldehyde with DEACD and aniline or 4-flouroaniline under the same reaction conditions, there is no reaction occurred, this may be attributed to the acid sensitivity of the aldehyde (2-furfuraldehyde). The experimental results are ▶ Table 3. included in ● ▶ Fig. 3, ● Structure of the synthesized products 1–16 was established on the basis of their spectral data and elemental analyses. Thus, IR spectra exhibited the absorption bands around 1 721, 1 687 cm − 1, corresponding to 2C = O and around 3 302 cm − 1 corresponding to NH groups. The mass spectra of the products showed their respective [M + ] peaks. Moreover, their 1H NMR spectra revealed
Table 3 Reaction times, yields and cytotoxic activity of ethyl 2-(aryl)-4-(substitutedamino)-5-oxo- 2,5-dihydrofuran-3-carboxylate derivatives.
NHAr'
C2H5O Ar Compd. No. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 Doxorubicin
Ar
Ar’
C6H4F-4 C6H4F-4 C6H4F-4 C6H4F-4 C6H4F-4 C6H4F-4 C6H4F-4 C6H4F-4 C6H4F-4 C6H4F-4 C6H4Br-3 C6H4Br-3 C6H4Br-3 C6H4Br-3 C6H4Br-3 2-thienlyl
Time
C6H5 C6H4(CH3)-4 C6H4(OC2H5)-4 C6H4F-4 C6H4Cl-4 C6H4Br-4 C6H4(NO2)-3 n-C4H9 CH2Ph 2-thiazolyl C6H5 C6H4Cl-4 C6H4Br-4 C6H4(NO2)-3 n-C4H9 CH2Ph
Yield
11 10 10 14 15 16 17 17 17 15 14 15 15 16 16 15
IC50 µM of Cytotoxicity
85 89 90 82 81 80 78 73 74 72 85 80 79 76 72 65 0.007
O
COOEt Ar'NH2
ArCHO
O
O
COOEt
SSA/EtOH 85 °C
HN Ar'
C2H5O Ar
O
HepG2
MCF-7
CACO
0.002 0.019 0.002 0.201 0.227 0.210 0.208 0.212 0.188 0.212 0.168 0.149 0.158 0.169 0.227 – 0.005
0.002 0.020 0.019 0.205 0.237 0.229 0.208 0.030 0.201 0.218 0.188 0.182 0.141 0.170 0.249 – 0.004
> 0.3 > 0.3 > 0.3 > 0.3 > 0.3 > 0.3 > 0.3 > 0.3 > 0.3 > 0.3 > 0.3 > 0.3 > 0.3 > 0.3 > 0.3 –
Fig. 3 Synthesis of ethyl 2-(aryl)-4-(subamino)-5oxo- 2,5-dihydrofuran-3-carboxylate derivatives.
O
1-16 1 Ar = C 6 H4F-4 2 Ar = C 6 H4F-4 3 Ar = C 6 H4F-4 4 Ar = C 6 H4F-4 5 Ar = C 6 H4F-4 6 Ar = C 6 H4F-4 7 Ar = C 6 H4F-4 8 Ar = C 6 H4F-4
Ar' = C 6H5 Ar' = C 6H4(CH3)-4 Ar' = C 6H4(OC 2H5)-4 Ar' = C 6H4F-4 Ar' = C 6H4Cl-4 Ar' = C 6H4Br-4 Ar' = C 6H4(NO2)-3 Ar' = n-C 4H9
9 Ar = C 6H4 F-4 1 0 Ar = C 6H4 F-4 11 Ar = C 6H4Br-3 12 Ar = C 6H4Br-3 13 Ar = C 6H4Br-3 14 Ar = C 6H4Br-3 15 Ar = C 6H4Br-3 1 6 Ar = 2-thienyl
Ar' = CH2C 6 H5 Ar' = 2-thaiazolyl Ar' = C6H5 Ar' = C 6H4C l-4 Ar' = C6H4Br-4 Ar' = C6H4(NO 2)-3 Ar' = n-C4H9 Ar' = CH2C 6H5
Basyouni WM et al. Furanones as Cytotoxic Agents … Drug Res 2015; 65: 473–478
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O
476 Original Article
Basyouni WM et al. Furanones as Cytotoxic Agents … Drug Res 2015; 65: 473–478
The presence of thiazole nucleus does not improve the cytotoxic activity and showed slight activity against HEPG2 and MCF7 cell lines (IC50 about 0.21 µM). For instance, compounds 11–15, Ar was 3-bromophenyl moiety and Ar' were Ph; 11, C6H4Cl-4; 12, C6H4Br-4; 13, C6H4(NO2)-3; 14, n-C4H9; 15. In general, the mean values of IC50 obtained for these compounds suggest that: replacement of 4-fluorophenyl moiety by 3-bromophenyl moiety proved to be detrimental to cytotoxic activity. Introduction of bromophenyl moiety showed slight activity against HEPG2 and MCF7 cell lines (IC50 0.14– 0.24 µM).
Experimental Section
▼
All melting points were determined on an electrothermal Gallenkamp apparatus and are uncorrected. Analytical TLC was performed with silica gel GF254 plates, and the products were visualized by UV detection. 1H, 13C and NMR spectra were recorded on a Bruker AVANVE 600 NMR spectrometer {1H 600.13 MHz; 13C 150.91 MHz equipped with TBI probe head. Samples were measured in DMSO-d6 1H NMR (500 MHz) spectra were recorded in DMSO-d6. Chemical shifts (δ) are reported in ppm using TMS as internal standard and spin-spin coupling constants (J) are given in Hz. The mass spectra (EI) spectra were measured on an HP 5988A spectrometer by direct inlet at 70 eV. Elemental analyses were carried out by the Micro-analytical Laboratory, National Research Centre, Cairo, Egypt.
General procedure for synthesis of 3, 4, 5-substituted furan-2(5H)-one derivatives
A mixture of aldehyde (2.0 mmol), amine (2.0 mmol), diethylacetylene-dicarboxylate (2.0 mmol), and SSA (0.11 g) was dissolved in EtOH (5 mL) after which the reaction mixture was heated at 85 °C until completion of the reaction as indicated by TLC. Upon and on completion, CH2Cl2 was added and catalyst was removed by filtration. Filtrates were washed with saturated NaHCO3 (aq) and brine, dried with anhydrous Na2SO4, and concentrated to dryness. Finally, the residue was purified by silica gel chromatographic methods to obtain the following pure product.
Ethyl 2-(4-fluorophenyl)-5-oxo-4-(phenylamino)-2,5-dihydrofuran-3-carboxylate (1): pale yellow solid; mp = 179–181 °C; Rf = 0.17 (28 % ethyl acetate in petroleum ether); IR: ν/cm − 1: 3 295 (NH), 1 718, 1 664 (C = O); 1H NMR: δ/ppm = 1.04 (t, J = 6.90 Hz, 3H, CH2CH3), 3.97 (q, J = 6.90 Hz, 2H, CH2), 6.02 (s, 1H, CH furanone), 6.99–7.51 (m, 8H, ArH), 11.79 (br, 1H, NH); MS (m/z, %): 341 (M + , 100); Anal. Calcd. for C19H16FNO4 (341.11): C, 66.86; H, 4.72; N, 4.10; Found: C, 66.58; H, 4.97; N, 4.22. Ethyl 2-(4-fluorophenyl)-5-oxo-4-(p-tolylamino)-2,5-dihydrofuran-3-carboxylate (2): pale yellow solid; mp = 177–179 °C; Rf = 0.60 (33 % ethyl acetate in petroleum ether); IR: ν/cm − 1: 3 307 (NH), 1 727, 1 688 (C = O); 1H NMR: δ/ppm = 1.04 (t, J = 6.85 Hz, 3H, CH2CH3), 2.21 (s, 3H, CH3), 3.98 (q, J = 6.85 Hz, 2H, CH2), 6.00 (s, 1H, CH furanone), 6.99–7.39 (m, 8H, ArH), 11.67 (br, 1H, NH); MS (m/z, %): 355 (M + , 100); Anal. Calcd. for C20H18FNO4 (355.12): C, 67.60; H, 5.11; N, 3.94; Found: C, 67.30; H, 5.25; N, 3.80.
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4-flourophenyl (or 3-bromophenyl) at position-5 and various substituents at position-3. The cytotoxic activity of the synthesized compounds was evaluated against human hepatocellular carcinoma cell line (HEPG2), human breast cancer cell line (MCF7) and human colon adenocarcinoma cell line (CACO). Doxorubicin (CAS-23214–92–8) was used as a reference drug, which considers one of the most effective anticancer agent. Potential cytotoxicity of the compounds was tested using the method of ▶ Table 3. Using Skehan et al. [16]. IC50 value was summarized in ● the general structure provided in ● ▶ Table 3, certain aspects of the structure activity relationships for these compounds can be more clearly highlighted. As anticipated, a clear difference in cytotoxic activity was noted between compounds under investigation. The mean values of IC50 represented that: all tested compounds possessed IC50 > 0.3 µM against the growth of CACO, but some tested compounds possessed significant cytotoxic activity against the growth of HEPG2 and MCF7. For instance, compounds 1–10, where Ar was 4-flourophenyl moiety and Ar' were Ph; 1, C6H4(CH3)-4; 2, C6H4(OC2H5)-4; 3, C6H4F-4; 4, C6H4Cl-4; 5, C6H4Br-4; 6, C6H4(NO2)-3; 7, n-C4H9; 8, CH2Ph; 9, 2-thiazolyl; 10. Regarding the effect of Ar' group, it was evident that varying such a unit may have a dramatic effect on cytotoxic activity, which may be augmented or reduced depending on whether a matching or mismatching relationship exists with the Ar 'group. The type of the substitution on the benzene ring of Ar' moiety is important. It was noticed that the presence of electron donating group at the benzene ring or leaving benzene ring without substitution had a potent effect on cytotoxic activity. The presence of unsubstituted benzene ring (1) resulted in the highest cytotoxic activity among all the compounds investigated in this study. The presence of unsubstituted benzene moiety was exhibited significant antitumor activity against HEPG2 and MCF7 cell lines (IC50 values 0.002 and 0.002 µM, respectively) more than reference drug (IC50 0.007, 0.005 µM). Compound 3 with 4-ethoxyphenyl moiety showed significant antitumor activity (IC50 0.002 µM) more than reference drug (0.007 µM) against HEPG2 cell line and exhibited a good activity against MCF7 cell line (IC50 0.019 µM). Also, compound 2 (4-methylphenyl moiety) showed good activity against HEPG2 and MCF7 cell lines. The presence of electron withdrawing halogen-atom such as Cl and Br at the benzene ring had a detrimental effect on cytotoxic activity. Introduction of bromophenyl moiety in case of compound 6 resulted in the lowest cytotoxic activity among all the compounds investigated in this study. 4-Chlorophenyl, 5; 4-bromophenyl, 6 showed slight activity against MCF7 and HEPG2 cell lines (IC50 about 0.21 µM). The presence of 4-fluorophenyl moiety showed IC50 about 0.2 µM against HEPG2 and MCF7. Introduction of polar group such as nitro group at the benzene ring in case of compound 7 had a detrimental effect on cytotoxic activity. Compound 7 showed slight activity against MCF7 and HEPG2 cell lines (IC50 about 0.2 µM). When Ar' was replaced by alkyl moiety, such as n-butyl moiety in case of compound 8 a moderate activity against MCF7 cell line (IC50 0.03 µM) was observed with a slight activity against HEPG2 cell line (IC50 0.21 µM). The presence of CH2Ph moiety (compound 9) reflect a slight activity against HEPG2 and MCF7 cell lines (IC50 0.18 and 0.20 µM, respectively).
Original Article 477
Ethyl 2-(4-fluorophenyl)-4-(4-fluorophenylamino)-5-oxo-2,5dihydrofuran-3-carboxylate (4): white solid; mp = 153–155 °C. Rf = 0.26 (28 % ethyl acetate in petroleum ether); IR: ν/cm − 1: 3 299 (NH), 1 727, 1 690(C = O) cm − 1; 1H NMR: δ/ppm = 1.04 (t, J = 6.85Hz, 3H, CH2CH3), 3.99 (q, J = 6.85 Hz 2H, OCH2), 6.05 (s, 1H, CH furanone), 7.02–7. 59 (m, 8H, ArH), 11.78 (b, 1H, NH) ppm; MS (m/z, %): 359 (M + , 100); Anal. Calcd. for C19H15F2NO4 (359.10): C, 63.51; H, 4.21; N, 3.90; Found: C, 63.51; H, 4.21; N, 3.90. Ethyl 4-(4-chlorophenylamino)-2-(4-fluorophenyl)-5-oxo-2,5dihydrofuran-3-carboxylate (5): pale yellow solid; mp = 172– 174 °C. Rf = 0.48 (28 % ethyl acetate in petroleum ether); IR: ν/ cm − 1: 3 304 (NH), 1 730, 1 685 (C = O); 1H NMR: δ/ppm = 1.05 (t, J = 6.87Hz, 3H, CH2CH3), 3.98 (q, J = 6.87 Hz 2H, OCH2), 6.07 (s, 1H, CH furanone), 7.01–7.58 (m, 8H, ArH), 11.79 (br, 1H, NH); MS (m/z, %): 375 (M + , 76.29). Anal. Calcd. for C19H15ClFNO4 (375.07): C, 60.73; H, 4.02; N, 3.73; Found: C, 60.66; H, 4.12; N, 3.82. Ethyl 4-(4-bromophenylamino)-2-(4-fluorophenyl)-5-oxo-2,5- dihydrofuran-3-carboxylate (6): pale yellow solid; mp = 180– 182 °C; Rf = 0.68 (33 % ethyl acetate in petroleum ether); IR: ν/ cm − 1: 3 304 (NH), 1 731, 1 687 (C = O); 1H NMR: δ/ppm = 1.04 (t, J = 6.87Hz, 3H, CH2CH3), 3.98 (q, J = 6.87 Hz 2H, OCH2), 6.13 (s, 1H, CH furanone), 7.01–7.52 (m, 8H, ArH), 11.80 ( br, 1H, NH); MS (m/z, %): 419 (M + , 18.63); Anal. Calcd. for C19H15BrFNO4 (419.02): C, 54.30; H, 3.60; N, 3.33; Found: C, 54.47; H, 3.54; N, 3.22. Ethyl 2-(4-fluorophenyl)-4-(3-nitrophenylamino)-5-oxo-2,5- dihydrofuran-3-carboxylate (7): white solid; mp = 227–229 °C; Rf = 0.13 (33 % ethyl acetate in petroleum ether); IR: ν/cm − 1: 3 302 (NH), 1 721, 1 687 (C = O); 1H NMR: δ/ppm = 1.06 (t, J = 6.87 Hz, 3H, CH2CH3), 3.99 (q, J = 6.87 Hz 2H, CH2), 6.22 (s, 1H, CH furanone), 7.02–8.57 (m, 8H, ArH), 11.97 (br, 1H, NH); 13C NMR: 13.9 (CH3), 59.7 (CH -furanone), 59.8 (CH2), 112.5, 115.1, 115.3, 116.4, 119.7, 127.9, 129.9, 130.0, 130.1, 132.1, 137.2, 147.8, 152.2, 160.4, 161.8 (C = O), 164.3 (C = O); MS (m/z, %): 386 (M + , 17.20); Anal. Calcd. for C19H15FN2O6 (386.09): C, 59.07; H, 3.91; N, 7.25; Found: C, 59.14; H, 3.85; N, 7.19. Ethyl 4-(butylamino)-2-(4-fluorophenyl)-5-oxo-2,5-dihydrofuran-3-carboxylate (8): white solid; mp = 202–204 °C; Rf = 0.33 (28 % ethyl acetate in petroleum ether); IR: ν/cm − 1: 3 132 (NH), 1 681 (C = O) cm − 1; 1H NMR: δ/ppm = 0.76 ( t, J = 7.27 Hz, 3H, N-CH2CH2CH2CH3), 1.00 (t, J = 7.25 Hz, 3H, CH2CH3), 1.11 (m, 3H, N-CH2CH2CH2CH3), 1.32 (m, 3H, N-CH2CH2CH2CH3), 2.54 (m, 1H, N-CH.), 3.47 (m, 1H, N-CH), 3.96 (q, J = 7.25 Hz, 2H, OCH2), 5.20 (s, 1H, CH furanone), 7.13–7.21 (m, 4H, ArH), 11.57 (br, 1H, NH); 13 C NMR: 13.6 (CH3), 13.9 (CH3), 19.8 (CH2), 30.2 (CH2), 40.0 (CH2), 59.7 (CH-furanone), 61.0 (CH2), 112.6, 114.5, 115.7, 115.8, 129.4, 130.6, 157.6, 163.4 (C = O), 165.0 (C = O); MS (m/z, %): 321
(M + , 2.89); Anal. Calcd. for C17H20FNO4 (321.14): C, 63.54; H, 6.27; N, 4.36; Found: C, 63.49; H, 6.33; N, 4.29.
Ethyl 4-(benzylamino)-2-(4-fluorophenyl)-5-oxo-2,5-dihydrofuran-3-carboxylate (9): white solid; mp = 202–204 °C. Rf = 0.44 (33 % ethyl acetate in petroleum ether); IR: ν/cm − 1: 3 158 (NH), 1 678 (C = O); 1H NMR: δ/ppm = 0.98 (t, J = 6.85 Hz, 3H, CH2CH3), 3.67 (d, J = 15.3 Hz, 1H, N-CH), 3.95 (q, J = 6.85 Hz, 2H, CH2), 4.76 (d, J = 15.3 Hz, 1H, N-CH), 4.95 (s, 1H, CH furanone), 7.02–7.24 (m, 9H, ArH), 11.79 (br, 1H, NH); MS (m/z, %): 355 (M + , 0.32); Anal. Calcd. for C20H18FNO4 (355.12): C, 67.60; H, 5.11; N, 3.94; Found: C, 67.45; H, 5.35; N, 3.72 Ethyl 2-(4-fluorophenyl)-5-oxo-4-(thiazol-2-ylamino)-2,5-di hydrofuran-3-carboxylate (10): pale yellow solid; mp = 170– 172 °C. Rf = 0.55 (28 % ethyl acetate in petroleum ether); IR (KBr) υ: 3 171 (NH), 1 728,1 633 (C = O) cm − 1; 1H NMR: δ/ppm = 1.05 (t, J = 6.90 Hz, 3H, CH2CH3), 3.95 (q, J = 6.90 Hz 2H, OCH2), 6.09(s, 1H, CH furanone), 7.32–8.28 (m, 6H, ArH), 11.94 (b, 1H, NH); MS (m/z, %): 348(M + , 21.80); Anal. Calcd. for C16H13FN2O4S (348.06): C, 55.17; H, 3.76; N, 8.04 Found: C, 55.25; H, 3.61; N, 8.17 %. Ethyl 2-(3-bromophenyl)-5-oxo-4-(phenylamino)-2,5-dihydrofuran-3-carboxylate (11): pale yellow solid; mp = 187–189 °C; Rf = 0.37 (28 % ethyl acetate in petroleum ether); IR (KBr) υ: 3 302 (NH), 1 722,1 651 (C = O) cm − 1; 1H NMR: δ/ppm = 1.05 (t, J = 6.87 Hz, 3H, CH2CH3), 3.94 (q, J = 6.87 Hz, 2H, OCH2), 6.09 (s, 1H, CH furanone), 6.95–7.52 (m, 8H, ArH), 11.92 (b, 1H, NH) ppm; 13C NMR (150 MHz, DMSO) δ = 13.89 (CH3), 60.75 (CHfuranone), 61.41 (CH2), 112.72 (C), 122.12 (CH), 122.41 (C), 125.85 (CH), 126.03 (CH), 126.05 (CH), 129.10 (CH), 130.19 (CH), 130.76 (CH), 131.67 (CH), 135.91 (C), 137.49 (C), 156.66 (C), 162.65 (C = O), 164.89 (C = O); MS (m/z, %): 402(M + , 88.58); Anal. Calcd. for C19H16BrNO4 (401.03): C, 56.73; H, 4.01; N, 3.48 Found: C, 56.65; H, 4.11; N, 3.28 %. Ethyl 2-(3-bromophenyl)-4-(4-chlorophenylamino)-5-oxo-2,5dihydrofuran-3-carboxylate (12): pale yellow solid; mp = 178– 180 °C; Rf = 0.68 (33 % ethyl acetate in petroleum ether); IR: ν/ cm − 1: 3 307 (NH), 1 725, 1 691 (C = O); 1H NMR: δ/ppm = 1.06 (t, J = 6.87 Hz, 3H, CH2CH3), 4.02 (q, J = 6.87 Hz, 2H, CH2), 6.07 (s, 1H, CH furanone), 7.19–7.60 (m, 8H, ArH), 11.89 (br, 1H, NH); 13C NMR: 13.8 (CH3), 60.6 (CH-furanone), 61.4 (CH2), 112.8, 122.4, 122.9, 125.7, 129.1, 130.2, 130.6, 131.2, 131.7, 134.4, 137.1, 156.1, 162.6 (C = O), 164.6 (C = O); MS (m/z, %): 437 (M + H + 95.58); Anal. Calcd. for C19H15BrClNO4 (434.99): C, 52.26; H, 3.46; N, 3.21; Found: C, 52.35; H, 3.28 N, 3.32. Ethyl 2-(3-bromophenyl)-4-(4-bromophenylamino)-5-oxo-2, 5-dihydrofuran-3-carboxylate (13): white solid; mp = 189– 191 °C; Rf = 0.63 (33 % ethyl acetate in petroleum ether); IR (KBr) υ: 3 306 (NH), 1 725,1 663 (C = O) cm − 1; 1H NMR: δ/ppm = 1.06 (t, J = 6.85 Hz, 3H, CH2CH3), 4.02 (q, J = 6.85 Hz 2H, OCH2), 6.07(s, 1H, CH furanone), 7.46–7.54 (m, 8H, ArH), 11.88 (brs, 1H, NH); MS (m/z, %): 481.85(M + , 17.33); Anal. Calcd. for C19H15Br2NO4 (478.94): C, 47.43; H, 3.14; N, 2.91 Found: C, 47.26; H, 3.35; N, 2.79 %. Ethyl 2-(3-bromophenyl)-4-(3-nitrophenylamino)-5-oxo-2,5- dihydrofuran-3-carboxylate (14): white solid; mp = 196–198 °C; Rf = 0.44 (33 % ethyl acetate in petroleum ether); IR: ν/cm − 1: 3 320 (NH), 1 727, 1 684 (C = O) cm − 1; 1H NMR: δ/ppm = 1.07 (t, Basyouni WM et al. Furanones as Cytotoxic Agents … Drug Res 2015; 65: 473–478
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Ethyl 4-(4-ethoxyphenylamino)-2-(4-fluorophenyl)-5-oxo-2, 5-dihydrofuran-3-carboxylate (3): white solid; mp = 156–158 °C; Rf = 0.28 (28 % ethyl acetate in petroleum ether); IR: ν/cm − 1: 3 321 (NH), 1 717, 1 682 (C = O); 1H NMR: δ/ppm = 1.04 (t, J = 6.90 Hz, 3H, CH2CH3), 1.23 (t, J = 6.90 Hz, 3H, CH2CH3), 3.90 (q, J = 6.90 Hz 2H, CH2),, 3.96 (q, J = 6.90 Hz, 2H, OCH2), 5.96 (s, 1H, CH furanone), 6.78–7.37 (m, 8H, ArH), 11.69 (s, 1H, NH); MS (m/z, %): 385 (M + , 66.8); Anal. Calcd. for C21H20FNO5 (385.13): C, 65.45; H, 5.23; N, 3.63; Found: C, 65.50; H, 5.15; N, 3.60
478 Original Article
Ethyl 2-(3-bromophenyl)-4-(butylamino)-5-oxo-2,5-dihydrofuran-3-carboxylate (15): white solid; mp = 202–204 °C; Rf = 0.11 (28 % ethyl acetate in petroleum ether); IR: ν/cm − 1: 3 150 (NH), 1 680 (C = O) cm − 1; 1H NMR: δ/ppm = 0.76 (t, J = 7.25 Hz, 3H, N-CH2CH2CH2CH3), 1.01 (t, J = 7.25 Hz, 3H, CH2CH3), 1.03 (m, 3H, N-CH2CH2CH2CH3), 1.25 (m, 3H, N-CH2CH2CH2CH3), 2.55 (m, 1H, N-CH), 3.48 (m, 1H, N-CH), 3.92 (m, 1H, CH), 3.99 (m, 1H, CH), 5.21 (s, 1H, CH furanone), 7.15–7.47 (m, 4H, ArH), 11.69 (br, 1H, NH); MS (m/z, %): 381 (M + , 18.50); Anal. Calcd. for C17H20BrNO4 (381.06): C, 53.42; H, 5.27; N, 3.66; Found: C, 53.35; H, 5.21; N, 3.59 %. Ethyl 4-(benzylamino)-5-oxo-2-(thiophen-2-yl)-2,5-dihydrofuran-3-carboxylate (16): white solid; mp = 160–162 °C. Rf = 0.28 (33 % ethyl acetate in petroleum ether); IR: ν/cm − 1: 3 145 (NH), 1 681 (C = O) cm − 1; 1H NMR: δ/ppm = 1.01 (t, J = 6.87 Hz, 3H, CH2CH3), 3.79 (d, J = 15.25 Hz, 1H, N-CH), 3.99 (q, J = 6.87 Hz, 2H, OCH2), 4.80 (d, J = 15.30 Hz, 1H, N-CH), 5.29 (s, 1H, CH furanone), 7.07–7.28 (m, 8H, ArH), 11.85 (br, 1H, NH); MS (m/z, %): 343 (M + , 92.50); Anal. Calcd. for C18H17NO4S (343.09): C, 62.96; H, 4.99; N, 4.08; Found: C, 62.80; H, 4.66; N, 4.26.
Conflict of Interest
▼
The authors have no conflict of interest to disclose.
Basyouni WM et al. Furanones as Cytotoxic Agents … Drug Res 2015; 65: 473–478
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J = 6.87 Hz, 3H, CH2CH3), 3.99 (q, J = 6.87 Hz 2H, CH2), 6.21 (s, 1H, CH furanone), 7.15–8.60 (m, 8H, ArH), 12.06 (br, 1H, NH); MS (m/z, %): 447 (M + , 8.49); Anal. Calcd. for C19H15BrN2O6 (446.01): C, 51.03; H, 3.38; N, 6.26; Found: C, 51.09; H, 3.31; N, 6.20.
