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Microwave Assisted Reaction of Condensed Thiophenes With Electron Poor Olefins
Microwave Assisted Reaction of Condensed Thiophenes With Electron Poor Olefins
Journal of the Korean Chemical Society. 2003. Dec, 47(6): 591-596
Copyright © 2003, The Korean Chemical Society
  • Received : May 27, 2003
  • Published : December 20, 2003
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About the Authors
Khadijah M. Al-zaydi
Mohamed H. Elnagdi
Department of Chemistry; Faculty of Science; Cairo University , Giza-A. R. Egypt Reprint requested to Khadijah M. Al-Zaydi

Abstract
Aminothienopyridazines 1a, b and aminothienocoumarin 2 condensed with DMFDMA to yield amidines 3a, b and 4 . These compounds reacted with N-phenylmaleimide to yield 9 and 10 . On the other hand reacting 3a, b, 4, 18, 19 and 20 with maleic anhydride afforded only the formylated derivatives 5a, b, 6, 21, 22 and 23 respectively. The reaction of 3a, b with diethyl fumarate afforded 11 , formed most likely via hydrolysis of the amidine 14 during working up the reaction mixture. Irradiation of N -phenylmaleimide in microwave oven afforded [2+2] and [2+2+2] cycloaddition product.
Keywords
INTRODUCTION
The cycloaddition of condensed aminothiophenes with electron poor olefins has proved to be an efficient route to benzo-fused heteroaromatics. 1 - 5 It was suggested that presence of free amino groups is essential for reactivity of condensed aminothiophenes as dienes in the Diels-Alder reaction. It occurred to us to see if substituted condensed aminothiophenes could also act as active dienes in the Diels-Alder reaction if drastic reaction condition were used.
RESULTS AND DISCUSSION
Consequently we condensed amino thienopyridazines 1a, b and aminothienocoumarine 2 with dimethyl-formamide dimethylacetal (DMFDMA) and investigated the reactivity of the resulting amidines 3a, b and 4 toward electron-poor olefins. In polar solvents, only hydrolysis of the amidine moiety in 3 and 4 afforded 5 and 6 , respectively. Consequently we investigated the solventless addition of electronpoor olefins under a microwave irradiation, a technology that has been extensively utilized to affect Diels-Alder additions. 6 , 7 N -Phenylmaleimide under this condition reacted smoothly with 3a,b and 4 affording 9 and 10 , which are assumed to be formed via intermediacy of cycloadducts 7 , 8 which then loses formamidine to yield the final products 9, 10 ( 1 , 2 ).
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In contrast to this, the reaction of 3 with diethyl fumarate in microwave oven has afforded phthalazine derivatives 11 formed via initial formation of cycloadduct when treated with diethyl fumarate 12 then eliminate H 2 S to yield the non-isolable intermediate 14 which is then hydrolysed to afford the compound 11 . Compounds 14, 18, 19 and 20 were recovered unreacted when treated with diethyl fumarate under the similar condition. Under a variety of conditions, maleic anhydride failed to react with 3a, b, 4, 18, 19 and 20 . Only hydrolysis products to the formyl derivatives 5, 6, 21, 22 and 23 were observed ( 3 , 4 ). The difference in the behavior of 3 toward maleic anhydride and N -phenylmaleimide reflects their different activity as dienes in cycloaddition reactions. Consequently only hydrolysis occurs with maleic anhydride.
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Formation of 18, 19 and 20 has previously been reported via condensing 15, 16 and 17 with dimethylfomamide-dimethylacetal ( DMF DMA ). 8 So treatment of 18, 19 and 20 with maleic anhydride afforded 21, 22 and 23 respectively.
It is of value to report here that products of reacting aminothienocoumarine with N -phenylmaleimide were always contaminated with minor quantity of other products of MS=346 and 519. These were the only isolable products from the reaction of 18, 19 and 20 with N -phenylmalimide. The same results were also obtained on irradiating N -phenylmaleimide in microwave oven. It is assumed to be the products of, most likely, nonconcerted [2+2] dimerization of two molecules of N -phenylmaleimide and the concerted [2+2+2] trimerisation of three molecules of N -phenylmalimide and thus assigned structures 24 and 25 respectively. To our knowledge, it is the first reported dimerization and trimerization under N -phenylmaleimide in microwave irradiation ( 5 ). It seems that this reaction proceeds much faster than cycloaddition to the diene system in 18, 19 and 20 . So this is reason why cycloaddition reaction did not proceed with these compounds.
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- Experimental
All melting points were measured on Gallenkamp electrothermal melting point apparatus and are uncorrected. IR spectra were recorded as KBr pellets on a Pye Unicam SP 3-300 Spectrophotometer. 1 H NMR spectra were recorded in deuterated dimethylsulfoxide ( DMSO -d 6 ) or deuterated chloroform (CDCl 3 ) on either Varian Gemini ( 1 H NMR at 200 MHz) or Bruker DPX ( 1 H, 13 C NMR at 400 MHz) spectrometer using tetramethylsilane ( TMS ) as an internal reference and results are expressed as δ values. Mass spectra were performed on a Shimadzu GCMS-QP 1000 Ex mass spectrometer at 70 eV. Microwave irradiation was carried out using commercial microwave oven and irradiation power of 450 W. Elemental analyses were carried out at the Microanalytical center of Cairo University.
- General Procedure for the preparation of 3a, b, 4, 18, 19 and 20
Method A. N,N -Dimethylformamide dimethylacetal (0.12 mol) was added to each of ( 1a, b, 2, 15, 16, 17 ) (0.1 mol) in xylene and the reaction mixture was refluxed for 6 hours. The removal of solvent under reduced pressure yielded the crude product which was crystallized from ethanol. 8
Method B. Compound ( 1a, b, 2, 15, 16, 17 ) (0.1 mol) and dimethylformamide dimethylacetal (0.1 mol) was placed in the microwave oven and irradiated at full power for 5-7 mins then left to cool to room temperature, and the solid was collected and crystallized from ethanol.
- 5-(Dimethylaminomethylenamino)-4-oxo-3-phenyl-3,4-dihydro-thieno[3,4-d] pyridazine-1-carboxylic acid ethyl ester 3a
Compound 3a was obtained as green crystals (method A: 61%, method B: 90%) mp 153 ℃. Analysis for C 18 H 18 N 4 O 3 S (370.43): Calcd: C, 58.36; H, 4.90; N, 15.12% Found: C, 58.39; H, 4.91; N, 15.14%. IR (ν/cm -1 ): 1729(CO ester) 1711(ring CO), 1 H NMR (δ ppm): 1.38(t, 3H, CH 3 CH 2 ); 3.07(s, 3H, CH 3 -N); 3.10(s, 3H, CH 3 -N); 4.42(q, 2H, CH 2 ); 702-7.60(m, 5H, Ar-H); 7.27(s, 1H, thienyl H); 7.89 ppm (s, 1H, amidine H). ms: M + (370).
- 5-(Dimethylaminomethylenamino)-3-(4-methoxyphenyl)-4-oxo-3,4-dihydro-thieno[3, 4-d]pyridazine-1-carboxylic acid ethyl ester 3b
Compound 3b was obtained as yellow crystals (method A: 62%, method B: 92%) mp 147 ℃. Analysis for C 19 H 20 N 4 O 4 S (400.45): Calcd: C, 56.99; H, 5.03; N, 13.99. Found: C, 56.97; H, 5.11; N, 14.01%. IR (ν/cm -1 ): 1730(CO ester) 1710 cm -1 (ring CO), 1 H NMR (δ ppm): 1.39(t, 3H, CH 3 CH 2 ); 3.08(s, 3H, CH 3 -N); 3.10(s, 3H, CH 3 -N); 3.85(s, 3H, OCH 3 ); 4.42(q, 2H, CH 2 ); 6.93-7.00(m, 2H, Aryl H-3, 5); 7.28(s, 1H, thienyl H); 7.4-7.5(m, 2H, Aryl H-2, H- 6); 7.88 ppm(s, 1H, amidine H). 13 C NMR (δ ppm): 14.37 (CH 3 CH 2 ); 34.97 (CH 3 -N); 40.84 (CH 3 -N); 55.60 (OCH 3 ); 61.91(OCH 2 ); 112.29, 114.03, 114.18, 127.84, 128.80, 133.08, 134, 53, 156.51, (aromatic and heterocyclic carbon) 157.97 (amidine CH) and 158.91, 163.45 (2CO). ms: M + (400).
- 3-N,N-Dimethylaminothieno[3,4:3\, 4\]benzo[b]pyran-4-one 4
Compound 4 was obtained as green crystals (method A: 72%, method B: 93%) mp 148 ℃. Analysis for C 14 H 12 N 2 O 2 S (272.32): Calcd: C, 61.75; H, 4.44; N, 10.29. Found: C, 61.77; H, 4.45; N, 10.30%. IR (ν/cm -1 ): 1690 cm -1 (ring CO), 1 H NMR (δ ppm): 2.47 (s, 3H, CH 3 ); 2.51(s, 3H, CH 3 ); 7.13-7.7 ppm(m, 6H, Ar-H, thienyl H and amidine H). ms: M + (272).
- N-Benzothiazol-2-yl-N,N-dimethylformamidine 18
Compound 18 was obtained as colourless crystals (75%) mp 111 ℃. Analysis for C 10 H 11 N 3 S(205.28): Calcd: C, 58.51; H, 5.40; N, 20.47. Found: C, 58.57; H, 5.45; N, 20.30%. 1 H NMR (δ ppm): 3.02(s, 3H, CH 3 -N); 3.04(s, 3H, CH 3 -N); 7.13-7.65 (m, 4H, Ar-H); 8.28 ppm (s, 1H, amidine H). 13 C NMR (δ ppm): 35.12(CH 3 -N); 40.97(CH 3 -N); 120.58, 121.23, 122.85, 125.74, 133.33, 152.11(phenyl carbon), 156.54 (thiazole C-2) and 173.61 (amidine). ms: M + (205).
- N,N-Dimethyl-N-(5-phenyl-2H-pyrazol-3-yl) formamidine 19
Compound 19 was obtained as buff crystals (method A: 78%, method B: 89%) mp 175 ℃. Analysis for C 12 H 14 N 4 (214.27): Calcd: C, 67.27; H, 6.59; N, 26.15. Found: C, 67.31; H, 6.60; N, 26.17%. IR (ν/cm -1 ): 3200(NH) and 3074 cm -1 (CH), 1 H NMR (δ ppm): 2.97(s, 3H, CH 3 -N); 3.04(s, 3H, CH 3 -N); 6.13 (s, 1H, pyrazol H-4); 7.34-7.78 (m, 5H, Ar-H); 7.86 (s, 1H, amidine CH) and 11.9 ppm (br, 1H, NH). 13 C NMR (δ ppm): 34.94 (CH 3 -N); 40.66(CH 3 -N); 87.83 (pyrazolyl C-4); 125.48, 127.50, 128.60, 133.77 (phenyl carbon), 150.0 (pyrazolyl C-2); 153.0 (pyrazolyl C-5) and 155.27(amidine CH). ms: M + (214).
- N,N-Dimethyl-N-(2H-[1, 2, 4]triazol-3-yl)formamidine 20
Compound 20 was obtained as colourless crystals (method A: 76%, method B: 85%) mp 97℃. Analysis for C 5 H 9 N 5 (139.16): Calcd: C, 43.15; H, 6.52; N, 50.33. Found: C, 43.20; H, 6.51; N, 50.36%. IR (ν/cm -1 ): 3325(NH), 2980 cm -1 (CH), 1 H NMR(δ ppm): 2.96(s, 3H, CH 3 -N); 3.04(s, 3H, CH 3 -N); 7.96(s, 1H, amidine CH); 8.3 (s, 1H , trizol H-3); and 12.7 ppm (br, 1H, NH). ms: M + (139).
- Reaction of 3a, 3b, 4, 18, 19 and 20 with maleic anhydride
- General Procedure.
Method A. A mixture of each of ( 3a, b, 4, 18, 19, 20 ) (0.1 mol) and maleic anhydride (0.1 mol) was heated at 200 ℃ for 30-60 mins, left to cool and triturated with ethanol. The solid product, so formed, was collected by filtration and crystallized from ethanol.
Method B. A mixture of each of ( 3a, b, 4, 18, 19, 20 ) (0.1 mol) and maleic anhydride (0.1 mol) was placed in the microwave oven and irradiated at 450 W for 2-5 mins, then left to cool to room temperature, and the solid was collected and crystallized from ethanol.
- 5-Formylamino-4-oxo-3-phenyl-3,4-dihydrothieno [3, 4-d]pyridazine-1-carboxylic acid ethyl ester 5a
Compound 5a was obtained as green crystals (method A: 53%, method B, 2 min : 65%) mp 249- 250 ℃. Analysis for C 16 H 13 N 3 O 4 S (343.36): Calcd: C, 55.97; H, 3.82; N, 12.24. Found: C, 55.99; H, 3.91; N, 12.14%. IR (ν/cm -1 ): 3345(NH), 1731(CO ester) 1690(CO) and 1645 cm -1 (ring CO), 1 H NMR (δ ppm): 1.43(t, 3H, CH 3 ); 4.48(q, 2H, CH 2 ); 7.39-7.60 (m, 5H, Ar-H); 7.96 (s, 1H, thienyl H); 8.55 (s, 1H, CHO); 11.09 ppm (s, 1H, NH). 13 C NMR (δ ppm): 14.37 (CH 3 CH 2 ); 62.38 (OCH 2 ); 112.88, 115.71, 125.38, 126.03, 128.34, 128.99, 133, 96(aromatic and heterocyclic carbon) and 157.50, 158.95, 162.79(3CO). ms: M + (343).
- 5-Formylamino-3-(4-methoxyphenyl)-4-oxo-3, 4-dihydrothieno[3, 4-d]pyrida-zine-1-carboxylic acidethyl ester 5b
Compound 5b was obtained as yellow crystals (method A: 30%, method B, 2 min: 55%) mp 228-230 ℃. Analysis for C 17 H 15 N 3 O 5 S (373.38): Calcd: C, 54.68; H, 4.05; N, 11.25. Found: C, 54.67; H, 4.11; N, 11.28%. IR (ν/cm -1 ): 3340(NH), 1731(COester) 1690(CO) and 1678 cm -1 (ring CO), 1 H NMR (δ ppm): 1.39(t, 3H, CH 3 CH 2 ); 3.86(s, 3H, OCH 3 ); 4.43(q, 2H, CH 2 ); 7.11(m, 2H, Aryl H-3, 5); 7.49 (m, 2H, Aryl H-2, H-6); 8.02(s, 1H, thienyl H); 8.67(s, 1H, CHO); 11.72ppm (s, 1H, NH). ms: M + (373).
- 3-Formylaminothieno[3, 4:3, 4]benzo[b]pyran-4-one 6
Compound 6 was obtained as pale green crystals (method A: 52%, method B, 3 min: 89%) mp 227- 228 ℃. Analysis for C 12 H 7 NO 3 S (245.25): Calcd: C, 58.77; H, 2.88; N, 5.71. Found: C, 58.79; H, 2.91; N, 5.74%. IR (ν/cm -1 ): 3345(NH), 1693(CO) and 1679 cm -1 (ring CO), 1 H NMR (δ ppm): 6.95-7.52 (m, 5H, Ar-H); 8.38 (s, 1H, CHO); 11.01 ppm (s, 1H, NH). ms: M + (245).
- N-Benzothizol-2-ylformamide 21
Compound 21 was obtained as green crystals (method A: 30%, method B, 3 min: 62%) mp 165 ℃. Analysis for C 8 H 6 N 2 OS (178.21): Calcd: C, 53.92; H, 3.39; N, 15.72. Found: C, 53.97; H, 3.40; N, 15.80%. 1 H NMR (δ ppm): 7.14-7.68(m, 4H, Ar-H); 8.58 (s, 1H, CHO) and 11.12 ppm (s, IH, NH). ms: M + (178).
- N-(5-Phenyl-2H-pyrazol-3-yl)formamide 22
Compound 22 was obtained as beige crystals (method A: 14%, method B, 5 min: 35%) mp 224-226 ℃. Analysis for C 10 H 9 N 3 O (187.20): Calcd: C, 64.16; H, 4.85; N, 22.45. Found: C, 64.21; H, 4.89; N, 22.47%. 1 H NMR (δ ppm): 6.43 (s, 1H, pyrazol H-4); 7.34-7.79 (m, 5H, Ar-H); 8.21 (s, 1H, CHO) 11.01 (1s, 1H, NH) and 12.01 ppm (1s, 1H, NH). ms: M + (214).
- N-(2H-[1, 2, 4]Triazol-3-yl)formamide 23
Compound 23 was obtained as beige crystals (method A: 25%, method B, 5 min: 45%) mp 254 ℃. Analysis for C 4 H 6 N 4 O(126.12): Calcd.: C, 38.09; H, 4.80; N, 44.42. Found: C, 38.10; H, 4.81; N, 44.46%. 1 H NMR (δ ppm): 8.3 (s, 1H , trizol H-3); 9.72(s, 1H, CHO); 10.09 (1s, 1H, NH) and 12.7 ppm (1s, 1H, NH). ms: M + (139).
- General Procedure for the preparation of 9a, b and 10
Method A. A mixture of each of ( 3a, b, 4 ) (0.1 mol) and N-phenylmaleimide (0.1 mol) was heated at 200 ℃ for 1hr, left to cool and triturated with ethanol the solid product, so formed, was collected by filtration and crystallized from ethanol.
Method B. A mixture of each of ( 3a, b, 4 ) (0.1 mol) and N-phenylmaleimide (0.1 mol) was placed in the microwave oven and irradiated at 450 W for 15-28 mins then left to cool to room temperature, and the solid was collected and crystallized from ethanol.
Compound 9a. was obtained as green crystals (method A: 52%, method B, 15 min: 63%) mp 185 ℃. Analysis for C 25 H 17 N 3 O 5 (439.42): Calcd: C, 68.33; H, 3.90; N, 9.56. Found: C, 68.10; H, 4.00; N, 9.650%. IR (ν/cm -1 ): 1728 (CO ester) 1710, 1695 (CO) and 1642 (ring CO), 1 H NMR (δ ppm): 1.43 (t, 3H, CH 3 ), 4.2 (q, 2H, CH 2 ), 7.16-7.76 (m,10H, Ar-H); 8.09 (s, 1H, H-9); 9.01 ppm (s, 1H, H-5) 13 C NMR (δ ppm): 14.27 (CH 3 CH 2 ); 62.85 (OCH 2 ); 107.79, 110.12, 116.47, 125.94, 126.46, 128.35, 128.93, 129.12, 129.28, 129.38, 131.34, 134.79, 136.83, 137.99, 140.46, 148.68, 160.87 (aromatic and heterocyclic carbon) and 162.91, 165.96, 168.17, 198.20 (4CO). ms: M + (439).
Compound 9b. was obtained as dark yellow crystals (method A: 58%, method B, 28 min: 67%) mp 158 ℃. Analysis for C 26 H 20 N 4 O 6 (469.13): Calcd: C, 66.52; H, 4.08; N, 8.95. Found: C, 66.45; H, 4.17; N, 9.82%. IR (ν/cm -1 ): 1738 (CO ester) 1695 (CO) and 1642 (ring CO), 1 H NMR (δ ppm): 1.43 (t, 3H, CH 3 ); 3.67 (s, 3H, OCH 3 ); 4.2 (q, 2H, CH 2 ); 7.02-7.52 (m, 9H, Ar-H); 8.08 (s, 1H, H-9); 9.03 ppm (s, 1H, H-5); ms: M + (469).
Compound 10. was obtained as oily crystals (method A: 72%, method B, 28 min: 88%) mp 165 ℃. Analysis for C 21 H 11 NO 4 (341.07): Calcd: C, 73.90; H, 3.25; N, 4.10. Found: C, 73.87; H, 3.31; N, 4.13%. IR (ν/cm -1 ): 1710 (ring CO) 1695 cm -1 (amide CO), 1 H NMR (δ ppm): 7.2-7.68 (m, 9H, Ar-H), 7.99 (s, 1H, H-7), 8.50 ppm (s, 1H, H-11). ms: M + (341).
- Triethyl 5-amino-3, 4-dihydro-4-oxo-3-phenylphtha lazine-1,6,7-tricarboxylate 11
A mixture of 3a (0.1 mol) and diethyl fumarate (0.1 mol) was placed in the microwave oven and irradiated at 450 W for 2 min, then left to cool to room temperature, and the solid was collected and crystallized from ethanol.
Compound 11. was obtained as dark red crystals (52%), mp 228 ℃. Analysis for C 23 H 23 N 2 O 7 (453.44): Calcd: C, 60.92; H, 5.11; N, 9.27. Found: C, 60.89; H, 5.14; N, 9.29 %. IR (ν/cm -1 ): 3505 and 3320 (NH 2 ), 1745, 1714, 1710 (ester CO) and 1673 (ring CO), 1 H NMR (DMSO-d 6 δ ppm): 1.19-1.44 (m, 9H, 3CH 3 ); 3.44 (s, 2H, NH 2 ); 4.20-4.42(m, 6H, 3CH 2 ); 7.25-7.60 (m, 5H, Ar-H); 8.15 ppm(s, 1H, H-8). ms: (M + +1) (454).
- 2, 5-Diphenyltetrahydrocyclobuta[1,5-c; 3,4-c/]dipyrrole-1,3,4,6-tetraone 24 and 2,5,8-Triphenylhexahydro-2,5,8-triazatrindene-1, 3, 4, 6, 7, 9-hexanone 25
Method A. N -phenylmaleimide was heated at 200 ℃ for 1 hr, left to cool and triturated with ethanol the solid product, so formed, was collected by filtration and crystallized from ethanol.
Method B. N-phenylmaleimide (0.1 mol) was placed in the microwave oven and irradiated at 450 W for 5 mins, then left to cool to room temperature, and the solid was collected and crystallized from ethanol.
Compound 24. was obtained as pink crystals (method A: 52%, method B: 60%) mp 252 ℃. Analysis for C 20 H 14 N 2 O 4 (346.34): Calcd: C, 69.36; H, 4.07; N, 8.09. Found: C, 69.40; H, 4.09; N, 8.12%. 1 H NMR (δ ppm): 3.64-3.66 (m, 4H, H-cyclobu- tane) and 6.83-7.64 ppm (m, 10H, Ar-H). 13 C NMR (δ ppm): 32.4 (cyclobutane carbon); 120.4, 124.1, 128.7, 140.8(aromatic carbon) 175.20 (CO). ms: M + (346).
Compound 25. was obtained as beige crystals (method A: 50%, method B: 64%) mp 275 ℃. Analysis for C 30 H 21 N 3 O 6 (519.50): Calcd: C, 69.36; H, 4.07; N, 8.09. Found: C, 69.39; H, 4.10; N, 8.10%. 1 H NMR (δ ppm): 2.88-3.03 (m, 6H, H-cyclohex-ane) and 6.86-7.67 ppm (m, 15H, Ar-H). 13 C NMR(δ ppm): 29.4 (cyclohexane carbon); 120.4, 124.1, 128.7, 140.8 (aromatic carbon) 173.80 (CO). ms: M + (519).
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