Reactions of 2,4-diphenylbutadiene-1,4-sultone with some 1,2- and 1,3-nitrogen binucleophiles

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1 General Papers ARKIVC 206 (iii) 5-22 Reactions of 2,4-diphenylbutadiene-,4-sultone with some,2- and,3-nitrogen binucleophiles Korany A. Ali, a * Anne Jäger, b and Peter Metz b a Applied rganic Chemistry Department, Center of Excellence for Advanced Science, ational Research Centre, 2622 Dokki, Giza, Egypt b Department of Chemistry, rganic Chemistry, Technical University Dresden, 0062 Dresden, Germany kornykhlil@gmail.com DI: Abstract Treatment of 2,4-diphenylbutadiene-,4-sultone with hydrazine in boiling Et gives -amino- 2,4-diphenyl--pyrrole. n treatment of 2,4-diphenylbutadiene-,4-sultone with phenyl hydrazine in glacial acetic acid, 4,5-dihydro-5-methyl-,3,5-triphenyl--pyrazole was isolated. n the other hand, 2,4-diphenylbutadiene-,4-sultone reacts with 4-,2,4-triazol-3-amine and 5-amino-3-phenyl--pyrazole to afford the novel heterocyclic compounds 2-(2,2-dioxo-4- phenyl-3,4-dihydro-8-2λ 6 -[,2,4]triazolo[5,-c][,2,4]thiadiazin-4-yl)--phenylethan--one, the structure of which was established by X-ray crystallography, and 2-(2,2-dioxo-4,7-diphenyl-3,4- dihydro-6-pyrazolo[5,-c][,2,4]thiadiazin-4-yl)--phenylethan--one. Keywords:,4-Dienic sultone, nitrogen binucleophiles, 2-aminopyrazole, 2-amino-,2,4-triazole Introduction Sultones are valuable compounds containing the -S 2 -- group as part of a ring, i.e. an internal ester of a hydroxy-sulfonic acid. These heterocycles can react with a variety of nucleophilic compounds to introduce an alkyl sulfonic acid group. Whereas sultones are sulfur analogues of lactones, they often behave differently when reacting with nucleophiles. Lactones are cleaved at the acyl-oxygen bond and behave as acylating agents, whereas sultones are cleaved at the carbon-oxygen bond and behave as sulfoalkylating agents. 2-4 There are few reports on reactions of,3-dienic δ-sultones. 5-7 To the best of our knowledge, the reactivity of sultones, especially of 2,4-disubstituted butadiene-,4-sultones, towards,2- and,3-binucleophiles has not yet been reported. In view of this, and in continuation of our current interest in the chemistry of,2- and,3-binucleophiles towards various types of dienophile, 8- the goal of the present study was the Page 5

2 General Papers ARKIVC 206 (iii) 5-22 examination of the reactivity of 2,4-diphenylbutadiene-,4-sultone towards selected,2- and,3- binucleophiles. Results and Discussion The reaction of 2,4-diphenylbutadiene-,4-sultone (strictly, 4,6-diphenyl-,2-oxathiin 2,2- dioxide) () with hydrazine hydrate was carried out in boiling Et. The progress of the reaction was monitored by TLC, which showed that conversion of the starting material was complete after 0 h. The structure of the product, separated using column chromatography (n-hexane/ethyl acetate-9/), is proposed to be -amino-2,4-diphenyl--pyrrole (2) (Scheme ) on the basis of its spectroscopic data. The MR spectrum of compound 2 revealed the presence of a signal at 5.45 ppm characteristic of an 2 group, and -C(3) and -C(5) of the pyrrole ring were observed as singlets at 6.55 and 7.46 ppm. Compound 2 has been reported previously, prepared from γ-bromodypnone. 2 S 2 2 Et reflux 47% 2 2 Scheme The formation of compound 2 is assumed to take place via nucleophilic attack by an amino group of the hydrazine at the carbon-oxygen bond in to form the non-isolable intermediates 3a and 3b leading to 2 via loss of 2 S 3 (Scheme 2). S 2 2 S 3 2 S S 3 2 3a 3b 2 Scheme 2 Filimonov and his group 3 have reported previously the reaction of 2,4-dinitrophenylhydrazine with 2,4-diphenylbutadiene-,4-sultone () in aqueous acetic acid to obtain Page 6

3 General Papers ARKIVC 206 (iii) 5-22 acetophenone 2,4-dinitrophenylhydrazone, formed by the reaction of acetophenone [from decomposition of the sultone in the water-acid mixture] with 2,4-dinitrophenylhydrazine. In the present study, the reaction of with phenylhydrazine was carried out in boiling glacial acetic acid for 8 h, and 2,5-dihydro-5-methyl-,3,5-triphenyl--pyrazole (4) was isolated after chromatographic separation (Scheme 3). S 2 Ac/ reflux - 2 S 3 4 5% Scheme 3 The structure of compound 4 was established on the basis of its spectroscopic data. The - MR spectrum of compound 4 revealed the presence of two characteristic signals at 2.42 and 7.34 ppm corresponding to C 3 and C-pyrazole protons, and in addition a signal at 3.2 ppm corresponding to the group. As presented in Scheme 4, the formation of compound 4 could occur via Michael addition of phenylhydrazine to the dienylsulfonate unit to give 5 followed by ring opening, loss of sulfur trioxide, proton transfer (arrows on 6) and a final ring closure (arrows on 7) to generate the dihydropyrazole system. S 2 Ac reflux S S + S Me +, Me Scheme 4 Aminoazoles as,3-binucleophiles are valuable building blocks for the synthesis of fused heterocycles. 8- They were used as Michael donors in reactions with electrophilic substrates, where the reaction was initiated by the attack of the 2 group onto an electron-deficient center Page 7

4 General Papers ARKIVC 206 (iii) 5-22 followed by cyclization via addition/elimination to give fused heterocycles. 0, The behavior of 2,4-diphenylbutadiene-,4-sultone () towards some,3-binucleophilic aminoazoles was investigated. Thus, treatment of with 4-,2,4-triazol-3-amine (8) in refluxing Et/DMF for 36 hours furnished a novel product identified as 2-(2,2-dioxo-4-phenyl-3,4-dihydro-8-2λ 6 - [,2,4]triazolo[5,-c][,2,4]thiadiazin-4-yl)--phenylethan--one (9) (Scheme 5) in 33% yield. Using microwave irradiation improved the yield of 9 to 47% after 45 minutes. S + 2 Et/DMF Method A: reflux for 36 h S 33% 8 Method B: Microwave for 45 minutes 9 47% Scheme 5 The formation of compound 9 can be explained on the basis of an initial sulfonamide formation via addition of the exocyclic 2 in 4-,2,4-triazol-3-amine (8) on the sulfonate function in followed by protonation of the dienolate and then intramolecular aza-michael addition as outlined in Scheme 6 to afford compound 9. S + 2 S S Scheme 6 The structure of compound 9 was established on the basis of the spectroscopic data. The MR spectrum revealed the presence of signals characteristics for two C 2 groups (doublets at 3.82 and 4.22 ppm), C-triazole (singlet at 7.56 ppm) and a D 2 -exchangeable (8.3 ppm). The mass spectrum of compound 9 had a peak at m/z 368 corresponding to its molecular ion. Moreover, the structure of compound 9 was unambiguously solved by X-ray diffraction analysis as shown in Figure. Page 8

5 General Papers ARKIVC 206 (iii) 5-22 C6 C7 C8 C20 C2 C22 C5 C4 C3 C3 4 5 C0 C9 C C24 C23 C2 2 S C6 2 9 C8 7 Figure. X-Ray crystal structure of compound 9. The reaction of 2,4-diphenylbutadiene-,4-sultone () with 5-amino-3-phenyl--pyrazole (), was carried out in boiling Et/DMF. The progress of the reaction was monitored by TLC, which showed that conversion of the starting materials was complete after 26 hours improved to 49% yield after 20 minutes using microwave heating (Scheme 7). The structure of the product is proposed to be 2-(2,2-dioxo-4,7-diphenyl-3,4-dihydro-6-2λ 6 - pyrazolo[5,-c][,2,4]thiadiazin-4-yl)--phenylethan--one (2) on the basis of the spectroscopic data. The IR spectrum of the later product revealed absorption bands at 36 and 662 cm - corresponding to and C= groups, respectively. The MR spectrum revealed the presence of signals characteristic for two C 2 groups (doublets at 3.6, 4.0 ppm), C-pyrazole (singlet at 6.80 ppm) and a D 2 -exchangeable (8.9 ppm). Its mass spectrum had a peak at m/z 443 corresponding to the molecular ion. S + 2 Et/DMF Method A: reflux for 26h Method B : Microwave for 20 minutes S 2 Method A 39 % Method B 49% Scheme 7 Page 9

6 General Papers ARKIVC 206 (iii) 5-22 Experimental Section General. All melting points were measured on a Gallenkamp melting point apparatus (Weiss Gallenkamp, London, UK). The infrared spectra were recorded in potassium bromide discs on PyeUnicam SP 3300 or Shimadzu FT IR 80 PC infrared spectrophotometers (PyeUnicam Ltd. Cambridge, England and Shimadzu, Tokyo, Japan, respectively). The MR spectra were recorded on a Varian Mercury VX-300 MR spectrometer (Varian, Palo Alto, CA, USA). MR spectra were run at 300 Mz and 3 C MR spectra were run at Mz in deuterated chloroform (CDCl 3 ) or dimethyl sulfoxide (DMS-d 6 ). Chemical shifts are given in parts per million and were related to that of the solvent. Mass spectra were recorded on a Shimadzu GCMS-QP 000 EX mass spectrometer (Shimadzu) at 70 ev. Elemental analyses were recorded on Elementar-Vario EL (Germany) automatic analyzer. We prepared 2,4-diphenylbutadiene-,4- sultone () 3 and 3-phenyl--pyrazol-5-amine () 4,5 following the procedures reported in the literature. Microwave experiments were carried out using a CEM Discover LabmateTM microwave apparatus (300 W with ChemDriverTM Software). Reaction of 2,4-diphenylbutadiene-,4-sultone () with hydrazine hydrate. A mixture of hydrazine hydrate (60%,.5 ml) and 2,4-diphenylbutadiene-,4-sultone () (0.284 g, mmol) in Et (5 ml), was stirred at rt for 0.5 h then refluxed for 0 h. The reaction mixture was evaporated under reduced pressure and then purified using column chromatography (nhexane/ethyl acetate-9/-silica) to afford -amino-2,4-diphenyl--pyrrole (2). -Amino-2,4-diphenyl--pyrrole (2): yield 0.0 g (47%); mp:47-48 C [reported C]. white powder (Et); IR (KBr, cm - ): v max 3272 ( 2 ), MR (CDCl 3 ): δ 5.45 (br, s, 2, 2 ), 6.55 (s,, C-pyrrole--3), (m, 0, Ar-), 7.46 (s,, C-pyrrole-- 5). 3 C MR (CDCl 3 ): δ 98., 05.3, 5.3, 27.8, 28.4, 28.6, 28.7, 29.2, 30.0, 30., 33., 36.. MS m/z (%): 234 [M + ] (0), 233 (00), 222 (45), 206 (0), 77 (45). Anal. Calcd. for C (234.3): C, 82.02;, 6.02;,.96. Found: C, 82.22;, 6.7;,.89 %. Reaction of 2,4-diphenylbutadiene-,4-sultone () with phenylhydrazine. To a solution of the sultone (0.284 g, mmol) in glacial acetic acid (0 ml) was added phenylhydrazine (0.8 g,.5 mmol). The reaction mixture was refluxed for 8 h then left to cool, and 0 ml of 2 was added. The resulting yellowish solid precipitate was collected by filtration, washed with Et, dried, and then purified using column chromatography (n-hexane/ethyl acetate-8/2-silica) to afford 2,5-dihydro-5-methyl-,3,5-triphenyl--pyrazole (4). 2,5-Dihydro-5-methyl-,3,5-triphenyl--pyrazole (4): Yield (0.6 g, 5%); mp: C; yellowish-white powder (Et/DMF); IR (KBr, cm - ): v max 322 (). MR (CDCl 3 ): δ 2.42 (s, 3, C 3 ), 7.34 (s,, C-pyrazole), (m, 5, Ar-), 3.2 (s,, ). 3 C MR (CDCl 3 ): δ 23.3, 65.8, 95.,.4, 20.4, 25.3, 25.6, 26.2, 28.4, 28.3, 28.6, 28.8, 34., 42.6, 45.2, 52.. MS m/z (%): 33 (0), 32 [M + ] (75), 297 (00), 235 (45), 223 (24), 9 (40), 77 (33), Anal. Calcd. for C (32.4): C, 84.58;, 6.45;, Found: C, 84.65;, 6.52;, 8.9%. Page 20

7 General Papers ARKIVC 206 (iii) 5-22 Reactions of 2,4-diphenylbutadiene-,4-sultone () with heterocyclic,3-binucleophiles Method A. To a mixture of 2,4-diphenylbutadiene-,4-sultone () (0.284 g, mmol) and the appropriate heterocyclic amine ( mmol) (2-amino-,3,4-triazole (8), 5-amino-3-phenyl-pyrazole ()) in Et/DMF (20/5 ml), were added a few drops of Et 3. The resulting mixture was refluxed for h then allowed to cool to rt. The solid that formed was collected by filtration, washed with Et, dried and the components separated using column chromatography (n-hexane/etac-silica). Method B. A mixture of 2,4-diphenylbutadiene-,4-sultone () (0.284 g, mmol) and the appropriate heterocyclic amine ( mmol) in Et/DMF (20/2 ml), were mixed in a quartz vial and the mixture was then heated under microwave irradiating conditions at 20 C and 250 W for min. The solid that formed was collected by filtration, washed with Et, dried and finally the components separated using column chromatography (n-hexane/etac-silica) to afford first compound 9 and then compound 2. 2-(2,2-dioxo-4-phenyl-3,4-dihydro-8-2λ 6 -[,2,4]triazolo[5,-c][,2,4]thiadiazin-4-yl)-- phenylethan--one (9). Yield by method A: 0.2 g, (33%); method B: 0.7 g. (47%); light brown crystals (Et/DMF), mp C. IR (KBr, cm - ): v max 35 (), 680 (C=). MR (DMS-d 6 ): δ 3.74 (, d, J = 6.5), 3.82 (, d, J = 6.5), 4.22 (, d, J = 7.), 4.35 (, d, J = 7.), (m, 0, Ar-), 7.56 (d,, triazole--5), 8.3 (br.s,, ), 3 C MR (DMS-d 6 ): δ 45.33, 46.29, 64.9, 95.2, 25.44, 27.60, 27.90, 28.23, 28.75, 33.67, 36.28, 39.3, 4.35, MS m/z (%): 369 (2), 368 [M + ] (5), 34 (5), 05 (95), 77 (00). Anal. Calcd. for C S (368.4): C, 58.68;, 4.38;, 5.2. Found: C, 58.73;, 4.3;, 5.35 %. Crystal data for compound 9. C S, M = 368.4, Monoclinic, a [Å] =.907 (), b [Å] =.243 (), c [Å] =6.067 (), α [ ] = 90.00, β [ ] = (), γ [ ] = 90.00, V [Å 3 ] = (2), T [ C] = 75 (2). Figure illustrates the structure as determined. Full data can be obtained on request from the CCDC. 6 2-(2,2-Dioxo-4,7-diphenyl-3,4-dihydro-6-pyrazolo[5,-c][,2,4]thiadizin-4-yl)--phenylethan--one (2). Yield by method A: 0.7 g (39%; method B 0.2 g, (49%); pale yellow crystals (Et/DMF), mp: C. IR (KBr, cm - ): v max 36 (), 662 (C=). MR (DMS-d 6 ): δ 3.6, 3.72 (2d, 2, C 2, J=6.6), 4.0, 425 (2d, 2, C 2, J=7.3), 6.8 (s,, pyrazole-), (m, 5, Ar-), 8.9 (s,, ), 3 C MR (DMS-d 6 ): δ 39.4, 58.3, 62.3, 25.6, 25.7, 26.0, 26.4, 27.3, 27.9, 28.3, 28.4, 28.8, 29.0, 33.7, 37.0, 46.5, 49.7, 64.3, 9.9. MS m/z (%): 444 (2), 443 [M + ] (00), 364 (70), 05 (23), 77 (30). Anal. Calcd. for C S (443.52): C, 67.70;, 4.77;, Found: C, 67.85;, 4.70;, 9.53 %. Page 2

8 General Papers ARKIVC 206 (iii) 5-22 Acknowledgements Financial support for this work was provided by DAAD Bilateral exchange program WAP-202. References and otes. Buglass, A. J.; Tillet, J. G. In The Chemistry of Sulfonic Acids, Esters and their Derivatives Eds.: Patai, S.; Rappoport, Z. John Wiley & Sons: ew York, 99, Chapter 9, p Roberts, W.; Williams, L. Tetrahedron 987, 43, Zeid,I.; Ismail, I. Liebigs Ann. Chem. 974, Shovan M., Chem. Rev. 202, 2, Mustafa, A. Chem. Rev. 954, 57, Yassin, S.; Ismail, I.; Abdel-Aleem, A.; Attia, A. Curr. Sci. 989, 58, Gaitsch, J., Rogachev, V. Zahel, M. Metz, P., Synthesis 204, 46, Ali, K.; Ragab, E.; Mloston, G.; Celeda, M.; Linden, A.; eimgartner,. elv. Chim. Acta 203, 96, Ali, K.; osni,.; Ragab, E.; Abd El-Moez, S. Arch. arm. 202, 345, Ali, K.; Elsayed, M.; Abdalghfar,. Arkivoc 20, (ii), Ali, K. eterocycles 202, 85, Potikha, L., Kovtunenko, V. Chem. eterocycl. Compd. 2007, 45, Rogachev, V..; Yusubov, M. S.; Filimonov, V. D. Russ. J. rg. Chem. 999, 35, Allen, G. R. J. rg. React. 973, 20, Kuecklander, U.; uehnermann, W. Arch. arm. 979, 32, Crystal data for compound 7 (ref. CCDC 06207) can be obtained on request from the director, Cambridge Crystallographic Data Center, 2 Union Road, Cambridge CB2 EW, UK. Page 22