Acta Chini. Slov. 2001, 48, 417-425. 417 BEHAVIOR OF 2(3#)- AND 2(5#)-FURANONES HAVING NO EXOCYCLIC DOUBLE BOND TOWARDS SOME NITROGEN NUCLEOPHILES Abdel-Sattar S. Hamad,* Hamed A. Derbala, Waleed A. El-Sayed, and Ahmed I. Hashem Department of Chemistry, Faculty of Science, University of Ain Shams, Abbassia 11566, Cairo, Egypt. Tel/Fax; (00) 202-4831836 e-mail; hamad@asunet.shams.eun.eg Received 06-02-2001 Abstract The behavior of 3-aryl-5-phenyl-2(3//)-furanones 1 and their 2(5//)-isomers 2 towards aniline, benzylamine, piperidine and ammonia was studied in an attempt to show the effect of position of the double bond on the reaction mode. It was found that either isomerization or amination occurred depending on the reaction conditions. Introduction 2(3//)- in addition 2(5//)-iuranones represent two important classes of heterocyclic compounds. The former is the precursors of a wide variety of other heterocycles. The synthesis and properties of 2(5//)-furanones have recently attracted much attention owing to the unique carbon skeleton of this class, which is widely spread in a variety of biologically active natural products. ' ' Results and Discussion In our earlier communications we have discussed the conversion of 3-aryl-5- phenyl-2(3//)-furanones la-c into 3(2//)-isothiazolones. We now report the successful studies of the reactions of 2(3//)-furanones la-c and their 2(5//)-isomers 2a-c with some primary and secondary amines such as ammonia, aniline, piperidine, and benzylamine under different conditions. 3-Aryl-5-phenyl-2(3//)-furanones la-c and 2a-c were obtained by ring closure of a-aryl-ß-benzoylpropionic acids using the procedure we described previously.6 The reaction of 2(3//)-furanones la-c with primary and secondary amines such as ammonia, aniline, benzylamine and piperidine was found to depend on the reaction conditions. Thus, when the reaction was conducted in the presence of polar and nonpolar solvents such as ethanol, diethyl ether and/or benzene, at different temperatures 0 °C, A-S. S. Hamad, H. A. Derbala, W. A. El-Sayed, A. I. Hashem: Behavior of2(3H)- and2(5H)-.... 418 Acta Chini. Slov. 2001, 48, 417-425. 25°C and boiling point of solvents, isomerization occurred to give the corresponding 2(5//)-furanones 2a-c. But, when the reaction was carried out in neat (without solvent), at the boiling point of amines, the corresponding 2(3//)-pyrrolones 3a-f were obtained in 79-91% yields as shown in Table 2. Surprisingly, the same 2(3//)-pyrrolones 3d-f was obtained from the reaction of 2(5//)-furanones 2a-c with aniline or benzylamine in neat at boiling point of each amine as shown in Scheme 1. /Ar x. ___/ ^>o Ph "Y R 3a-f Ar =C6H5-, C6H4OCH3(p-), C 6H4CI(p-); R= C6H5-, and C 6H4CH Reagent and condition i) Ammonia, aniline, benzylamine, pepridine/benzene, ethanol an ether at 0 °C, 25 °C and at b.p. of solvents, ii) Aniline and/or benzylamine in neat at b.p. Scheme 1 The H NMR spectrum of the 2(3//)-pyrrolones 3d-f exhibits two unexpected doublet signals centered at ô 3.6 and ô 5.2 for the same larger coupling constant (J = 15.2-15.6 Hz) are associated with the two-methylene (-N-CH2-) protons. The split of the two-proton of CH? into different resonance at ô 3.6 and ô 5.2 caused by electrical quadrupole moment effect on nitrogen and adjacent carbonyl. It was possible to identify three spots characteristic of 2(5//)-furanone 2a-c, 2(3//)-furanone la-c and 2(3//)- pyrrolones 3a-f were realized by performing TLC on an aliquot taken from the reaction mixture after 5 minutes. The isomerisation of 2(5//)-furanones 2a-c into 2(3//)-isomers la-c at boiling point of amines maybe represented by the following mechanistic pathway as shown in Scheme 2. A-S. S. Hamad, H. A. Derbala, W. A. El-Sayed, A. I. Hashem: Behavior of2(3H)- and2(5H)-.... Acta Chini. Slov. 2001, 48, 417-425. 419 2 1 Scheme 2 The reaction of 2(3//)-furanones la-c with piperidine was also studied at boiling point of piperidine in neat over 1-2 hours to give the a-aryl-ß-benzoyl-piperidyl propionamides 4a-c in 79-89% yields as illustrated in Table 2. The latter products 4a-c were also obtained from the reaction of 2(5//)-furanones 2a-c with piperidine at the same reaction condition. Piperidine firstly affects isomerisation of the 2(5//)-furanones into 2(3//)-isomers la-c, which then undergo ring opening to give the amides 4a-c, as illustrated as shown in Scheme 3. Û ... O \3^° heating at B.P Ph ^ J heating at B.P O 1 4 2 Ar = a = C6H5-,b = C6H4-OCH3 (p-), c = C6H4CL(p-) Scheme 3 The H NMR spectrum of a-aryl-ß-benzoylpiperidyl propionamides 4a-c exhibits two doublets of a doublet centered at ô 2.99- 3.05 and ô 3.89-4.10, attributed to the methylene protons (-CH?-). The methylene protons split the methine proton (-CH-C6H5) absorption into a doublet of a doublet at 4.47-4.56 with the areas in the ratio of 1:2. This due to the highr order spectrum effect (ABX tending to an AMX type). Experimental *H NMR spectra were recorded on Varian Plus 300 (300 MHz) or Bruker XL 300 (300 MHz) and on a Varian Gemini (200 MHz) instruments, the 13C NMR spectra (with DEPT 135) on a Bruker WP80 or XL 300 instrument. Infrared spectra listed as recorded 'neat' refer to a thin film of material on NaCl disks, and were taken on a Perkin Elmer 1600 FT-IR spectrometer. Melting points were measured on an electrothermal digital melting point apparatus and are uncorrected. The Rf values reported for TLC analyses A-S. S. Hamad, H. A. Derbala, W. A. El-Sayed, A. I. Hashem: Behavior of2(3H)- and2(5H)-.... 420 Acta Chini. Slov. 2001, 48, 417-425. were determined on Macherey-Nagel 0.25 mm layer fluorescent UV254 plates with the indicated solvent system. M-H-W Laboratories (Phoenix, AZ) at University of Minho, Braga, Portugal and microanalysis unit at University of Cairo, Egypt, performed elemental analyses. 3-Aryl-5-phenyl-2(3/7)-furanones (la-c) were prepared following the literature reports and our recent communications. The structures of the products were confirmed by H and C NMR spectrum and the spectral data is listed in Tables 1, 2 and 3. Table 1. Infrared (IR) and *H NMR (300 MHz) spectral data for compounds [(la-c), (2a-c), (3a-f) and (4a-c)]. Cpd No. Alkyl group (R) Aryl group (Ar) (IR)vmax (Nujol)/cm VC=0 VC=C 'HNMR (300 MHz, DMSO); ÖH la CgH5 1761(s), 1591(s) Ô = 6.32 (d, IH, J = 2.1 Hz), 7.44 (m, 8H), 7.93 (d, YR,J= 1.8 Hz), 7.95 (d, 1H,J = 1.8 Hz), 8.27 (d, IH, J =2.1 Hz) ppm. lb C6H5OCH3(p) 1759(s), 1595(s) Ô = 3.85 (s, 3H, Ar-OCHj), 6.01 (d, IH, J = 2.1 Hz), 6.96 (d, 2R,J=9 Hz, C6H4-OCH3), 7.42-7.27 (m, 5H, -C6H5), 7.51 (d, IH, J = 2.1 Hz, C6H4-OCH3), 7.89 (d, 2H, J = 9 Hz, C6H4-OCH3) ppm. lc -CöJtLiCI 1760(s), 1593(s) ô = 6.33 (d, IH, J = 1.8 Hz), 7.43-7.35 (m, 5H, -C6H5), 7.54 (d, 2H, J = 9 Hz, C6H4-C1), 7.99 (d, 2H, J= 9 Hz, C6H4-C1), 8.35 (d, IH, J= 1.8 Hz) ppm. 2a C6H5 1749(s), 1594(s) ô = 7.32-7.45 (m, 10H), 7.7 (d, IH, J= 2.2 Hz), 8.97 (d, IH, J= 2.2 Hz) ppm. 2b C6H4OCH3(p) 1748(s), 1599 (s) ô = 3.8 (s, 3H, Ar-OCä 7.3 (d, 2H, J= 8.7 Hz, C6H4-OCH3), 7.4-7.6 (m, 5H, -C6Es), 7.89 (d, 2H, J= 8.7 Hz, C6H4-OCH3), 8.5 (d, IH, J= 2.2 Hz), 8.9 (d, IH, J= 2.2 Hz) ppm. 2c -C6H4CI 1751(s), 1595(s) ô = 7.3-7.5 (m, 5H, -QH3), 7.6 (d, 2H, J = 8.9 Hz, C6H4-C1), 8.1 (d, 2H, J= 9 Hz, C6H4-Cl), 8.4 (d, IH, J= 2.1 Hz), 8.9 (d, YR,J = 2.1 Hz) ppm. 3a - CgH5 -CôH5 1664(s), 1596(s) ô = 6.2 (d, IH, J= 1.8 Hz, CH-Ar), 7.08-8.02 (m, 15H, 3C6H5-), 7.75 (d, IH, J= 1.8 Hz, C=CH) ppm. A-S. S. Hamad, H. A. Derbala, W. A. El-Sayed, A. I. Hashem: Behavior of2(3H)- and2(5H)-.... Acta Chini. Slov. 2001, 48, 417-425. 421 Table 1 Continued. 3b -C6H5 C6H4OCH3(p) 1681(s), 1595 (s) Ô = 3.77 (s, 3H, -OCH3), 5.1 (d, IH, J= 2.1 Hz, -CH-), 6.98 (d, 2H, J = 9 Hz, C6H4OCH3), 7.1-7.38 (m, 10H, 2QH5-), 7.47 (d, IH, J =2.1 Hz, C=CH-), 8.00 (d, 2H, J = 9 Hz, C6H4-OCH3) ppm. 3c - CgH5 -C6H4C1 (p-) 1672(s), 1594 (s) 5 = 5.7 (d, IH, J= 2.4 Hz, C=CH), 7.1-7.33 (m, 10H, 2C6H5-), 7.41 (d, 2H, J= 8.6 Hz, C6H4C1), 7.58 (dd, IH, J= 2.4 and 0.3 Hz, -CEbAr), 7.93 (d, 2H, J = 8.6 Hz, C6H4C1) ppm. 3d C6H4CH2- -C6H5 1681(s), 1596 (s) 5 = 3.77 (d, IH, J= 15.6 Hz, -NCTb-), 4.13 (d, IH, J= 15.6 Hz, -NCH2-), 5.1 (d, IH, J = 2.4 Hz, -CH-C6H5), 7.1-7.41 (m, 13H), 7.6 (d, lH,J=2.4Hz), 8.01 (d, 1H,J= 1.5 Hz), 8.04 (d, IH, 7=1.5 Hz) ppm. 3e CöH4CH2- C6H4OCH3(p) 1681(s), 1490 (s) 5 = 3.82 (s, 3H, -OCH3), 3.7 (d, 1 H, J = 15.2 Hz, -NCH2-), 4.86 (d, IH, J = 2.0 Hz, -CH-C6H5), 5.29 (d, IH, J= 15.2 Hz, -N-CHz-), 6.90 (d, 2H, J= 8.6 Hz, C6H4OCH3), 7.03 (d, IH, J= 2.0 Hz, C=CH-), 7.1-7.37 (m, 10H, 2 C6H5), 7.97 (d, 2H, J= 8.6 Hz, C6H4-OCH3) ppm. 3f C6H4CH2- -C6H4C1 (p-) 1669(s), 1609(s) 5 = 3.77 (d, IH, J= 15.3 Hz, -NCH2-), 4.98 (d, IH, J= 15.3 Hz, -NCH2-), 5.15 (d, IH, J = 2.1 Hz, -CH-C6H5), 7.08-7.41 (m, 10H, 2 C6H5), 7.49 (d, 2H, J = 8.4 Hz, C6H4-C1), 7.69 (d, IH, J =2.\ Hz, C=CH-), 8.09 (d, 2H, J= 8.4 Hz, C6H4-C1) ppm. 4a - CgH5 163 l(s), 1686(s) 5 = 0.85-1.44 (m, 6H, pip.), 3.05 (dd, 1H,J = 3.3 and 17.7 Hz, -CH2-), 3.25-3.50 (m, 4H, pip.), 3.95 (dd, IH, J= 10.8 and 17.7 Hz, -CH2-), 4.51 (dd, IH, J= 3.3 and 10.8 Hz, -CH-C6H5), 7.24-7.98 (m, 10H, 2 C6H5) ppm. 4b C6H4OCH3(p) 1629(s), 1680(s) 5 = 1.42-1.47 (m, 4H, pip.), 2.99 (dd, \K,J = 3.3 and 17.7 Hz, -CH2-), 3.15-3.47 (m, 6H, pip.), 3.72 (s, 3H, -OCH3), 3.89 (dd, IH, J = 10.5 and 17.7 Hz, -CB2-), 4.47 (dd, IH, J = 3.3 and 10.5 Hz, -CH-C6H5), 6.90 (d, 2H, J = 8.7 Hz, -C6H4-OCH3) 7.26 (d, 2H, J = 8.7 Hz, -C6H4-OCH3), 7.46-7.63 (m, 3H, -Otts), 7.95 (d, 2H, J= 1.2 and 8.4 Hz, -QHj) ppm. 4c -C6H4C1 (p-) 1634(s), 1683(s) 5 = 1.53 (m, 6H, pip.), 3.04 (dd, IH, J= 4.0 and 17.6 Hz, -CH2-), 3.4-3.6 (m, 4H, pip.), 4.1 (dd, IH, J = 9.6 and 17.6 Hz, -CH2-), 4.56 (dd, IH, J= 4.0 and 9.6 Hz, -CH-C6H5), 7.44 (d, 2H, J= 8.4 Hz, -C6H4C1) 7.24-7.7.55 (m, 3H, -C6H5), 7.95 (d, 2H, J = 8.4 Hz, -C6H4C1) ppm. A-S. S. Hamad, H. A. Derbala, W. A. El-Sayed, A. I. Hashem: Behavior of2(3H)- and2(5H)-.... 422 Acta Chini. Slov. 2001, 48, 417-425. 3-Aryl-5-phenyl-2(5/7)-furanones (2a-c); A mixture of a-aryl-ß-benzoylpropionic acids (1 mole), acetic anhydride (2 mole), acetic acid (2 mole) and few drops of concentrated sulfuric acid were heated under reflux for 1 hour. The reaction mixture was cooled on ice, filtered off and finally washed with ethanol to produce products in 75-82% yields, as illustrated in Table 2. 3-Aryl-l,5-diphenyl-2(3/7)-pyrrolones (3a-c): 3-Aryl-5-phenyl-2(3//)-furanones la-c (1.0 mole) and aniline (1.3 equivalent) were mixed in neat. A mixture was stirred and heated at boiling point of aniline for 1-2 hours and then cooled to precipitate. The precipitate was collected by filtration and recrystallized from the suitable solvent to yield pyrrolones 3a-c in 81-87% as shown in Table 2. These compounds were obtained also by starting from 3-aryl-5-phenyl-2(5//)-furanones 2a-c instead of 3-aryl-5-phenyl-2(3//)-furanones la-c, following the same procedure. The 3-aryl-l,5-diphenyl-2(3//)-pyrrolones 3a-c showed by direct comparison of m.p., and mixed m.p., TLC, and some spectral data to be identical with the authentic sample in all aspects. 3-Aryl-l-benzyl-5-phenyl-2(3/7)-pyrrolones (3d-f); 3-Aryl-5-phenyl-2(3//)-furanones la-c (1.0 mole) and benzylamine (4 equivalent) were mixed in neat. Following the same method described above for preparing compound 3a-c. The white precipitate was collected by filtration and recrystallized from the suitable solvent to yield 1-benzylpyrrolones 3d-f in 79-91%), as illustrated in Table 2. These compounds were obtained also by reaction of 3-aryl-5-phenyl-2(5//)-furanones 2a-c with benzylamine following the same procedure described above. 3-Aryl-l-benzyl-5-phenyl-2(3//)-pyrrolones 3d-f showed by direct comparison of m.p., and mixed m.p., TLC, and some spectral data to be identical with the authentic sample in all aspects. D-Aryl-E-benzoyl-piperidyl propionamides (4a-c): A suspension of 3-aryl-5-phenyl-2(3//)-furanones la-c (1.0 mole) with piperidine (1.5 equivalent) in neat. The suspension mixture was stirred and heated at boiling point of piperidine for 2 hours. The reaction mixture was then cooled and poured on 5.0 g of ice with 1.0 jV HCl (25 mL). The A-S. S. Hamad, H. A. Derbala, W. A. El-Sayed, A. I. Hashem: Behavior of2(3H)- and2(5H)-.... Acta Chini. Slov. 2001, 48, 417-425. 423 precipitate was collected by filtration and recrystallized from the suitable solvent to yield propionamides 4a-c in 79-89%, as illustrated in Table 2. These compounds were obtained also by reaction of 3-aryl-5-phenyl-2(5//)-furanones 2a-c, following the same method described above. The a-aryl-ß-benzoyl-piperidyl propionamides 4a-c showed by direct comparison of m.p., and mixed m.p., TLC and some spectral data to be identical with the authentic sample in all aspects. Table 2. Yields and physical data for compounds [(la-c), (2a-c), (3a-f) and (4a-c)]. Cpd No. Alkyl group Aryl group m.p C Yield Recryst. Solv. MF Analysis [Calcd/found] C H N la lb lc C6H5 C6H4OCH, C6H5C1 110-112 133-135 125-127 45% 32% 31% Petrol. ether/ toluene C16H12O2 C17H14O3 C16H11CIO2 81.34/81.38 5.11/5.03 76.68/76.55 5.29/5.35 70.99/70.98 4.09/4.23 2a 2b 2c C6H, C6H4OCH, C6H5C1 156-158 175-177 168-170 75% 82% 82% C16H12O2 C17H14O3 C16HUC102 81.34/80.82 5.11/5.30 76.68/76.69 5.29/5.35 70.99/70.85 4.09/4.11 3a 3b 3c 3d 3e 3f C6Hs C6Hs C6Hs C6H5CH2-C6H5CH2-C6H5CH2- C6H5 C6H4OCH, C6H5C1 C6H5 C6H4OCH3 C6H4C1 201-203 136-138 184-186 147-148 157-158 120-121 81% 87% 86% 79% 81% 91% EtOH C22H17NO C23H19NO2 C22H16C1N0 C23H19NO C24H21NO2 C23Hi8ClNO 84.86/84.82 5.50/6.24 4.49/3.91 80.91/80.65 5.60/6.19 4.10/3.89 76.40/76.46 4.66/4.51 4.05/4.40 84.89/84.86 5.88/5.81 4.30/4.44 81.10/81.13 5.95/5.98 3.94/4.01 76.76/76.56 5.04/5.03 3.89/3.49 4a 4b 4c C6H5 C6H4OCH, C6H4C1 115-117 120-122 199-201 89% 88% 79% Petrol. / EtOH C21H23NO2 C22H25NO3 C21H22CINO2 78.47/78.67 7.21/7.34 4.36/4.32 75.18/75.25 7.16/7.13 3.98/4.10 70.87/70.81 6.23/6.12 3.93/3.59 A-S. S. Hamad, H. A. Derbala, W. A. El-Sayed, A. I. Hashem: Behavior of2(3H)- and2(5H)-.... 424 Acta Chini. Slov. 2001, 48, 417-425. 13 Table 3; "C Chemical shifts for 3-Aryl-5-phenyl-2(3#)-furanones (la-b). 1a-b R = H and OCH3 Cpd. No. C-3 C-4 Ci-5 Ci-1' C-2' C-3' C-4' la 81.2 125.2 135.2 129.4 126.9 128.6 128.6 lb 81.5 114.0 145.0 135.1 121.8 126.6 128.6 Cpd. No. C=0 R C-l" C-2" C-3" C-4" la 150.4 — 129.3 126.9 129.1 129.0 lb 160.5 55 130.2 129.1 129.2 134.2 Table 3; 13C Chemical shifts for /V-benzyl-3,5-diphenyl-2(3#)-pyrrolone (3d). C-3 C-4 C-5 C-6 C=0 Ci-1' C-2' C-3' C-4' Ci-1" 90.5 126.6 148.1 43.1 166.6 137.7 126.2 128.9 128.3 136.5 C-2" C-3" C-4" Ci-1'" C-2'" C-3'" C-4'" 127.8 128.5 129.1 157.9 127.9 128.7 128.8 Conclusions The reactions of 2(3//)-furanones la-c with amines in solvent was conducted at 0 °C, 25 °C and also at refiuxing temperature. It was not possible to obtain any amides or pyrrolones but instead isomerization occurred to give the corresponding 2(5//)-isomers 2a-c, which was found to be unaffected under these conditions. It was realized that the amination occurred only in neat at boiling point of each amine. A-S. S. Hamad, H. A. Derbala, W. A. El-Sayed, A. I. Hashem: Behavior of2(3H)- and2(5H)-.... Acta Chini. Slov. 2001, 48, 417-425. 425 Acknowledgments The authors thank gratefully, Department of Chemistry, University of Minho, 4710 Braga, Portugal for facilities of obtained NMR spectra. References 1. Hashem, A. and Senning, A. "Advances in Heterocyclic Chemistry' 1999, 73, 275-93 2. Donnelly D. M. X. and Meegan, M. J. "Comprehensive Heterocyclic Chemistry1 Pergamon Press, Oxford, N.Y., 1984, Vol. 4, pp. 694-697. 3. Devon, T. C. and Scott, A. C. "Handbook of naturally occurring compounds'' Academic press, Inc. N. Y. 1975, volumes 1 and 2. 4. Ramza, J. and Zamojski, A. Carbohydr. Res. 1992, 228, 205. 5. Derbala, H. A.; Hamad, A-S. S.; El-Sayed, W. A.; Hashem, A.I. Phosphorus, Sulfur Silicon 2001, in press. 6. Ahmed, M. A.; Hashem, A. I.; Iskander, N. Rev. Roum. Chem. 1993, 38(1), 79-82. 7. Hamad, A-S. S. and Hashem, A. I. Molecules 2000, 5, 895-907. Povzetek Raziskali smo reaktivnost 3-aril-5-fenil-2(3//)-furanonov 1 in 2(5//)-izomerov 2 z anilinom, benzilaminom, piperidinom in amoniakom z namenom, da bi ugotovili vpliv reakcijskih pogojev na strukturio produktov. Ugotovili smo, da v odvisnosti od reakcijksih pogojev potece izomerizacija ali aminiranje. A-S. S. Hamad, H. A. Derbala, W. A. El-Sayed, A. I. Hashem: Behavior of2(3H)- and2(5H)-....