Efficient one-pot double Buchwald-Hartwig coupling reaction on 5-phenyl-4- phenylsulfonyl-2,3-dihydrofuran derivatives

Transcription

1 Efficient one-pot double Buchwald-artwig coupling reaction on 5-phenyl-4- phenylsulfonyl-,3-dihydrofuran derivatives Ahlem Bouhlel, Christophe Curti, mar Khoumeri, Patrice Vanelle To cite this version: Ahlem Bouhlel, Christophe Curti, mar Khoumeri, Patrice Vanelle. Efficient one-pot double Buchwald-artwig coupling reaction on 5-phenyl-4- phenylsulfonyl-,3-dihydrofuran derivatives. Tetrahedron Letters, Elsevier, 011, 5 (16), pp < /j.tetlet >. <hal > AL Id: hal ubmitted on 4 Jan 017 AL is a multi-disciplinary open access archive for the deposit and dissemination of scientific research documents, whether they are published or not. The documents may come from teaching and research institutions in France or abroad, or from public or private research centers. L archive ouverte pluridisciplinaire AL, est destinée au dépôt et à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

2 Efficient one-pot double Buchwald-artwig coupling reaction on 5-phenyl-4- phenylsulfonyl-,3-dihydrofuran derivatives Ahlem Bouhlel, Christophe Curti, mar Khoumeri, Patrice Vanelle* a Laboratoire de Pharmaco-Chimie Radicalaire, Faculté de Pharmacie, Universités d Aix-Marseille I, II, III-R, UMR 664, Laboratoire Chimie Provence, 7 Bd J. Moulin, Marseille Cedex 05, France. ABTRACT: We report a new and efficient method of conducting a one-pot double Buchwald-artwig coupling reaction on,3-dihydrofuran derivatives bearing two bromine atoms. This rapid and convenient synthesis allows us to access a great variety of original mixed dicoupled compounds. The strategy appears promising for combinatorial chemistry and pharmacomodulation studies. Keywords:ne-pot, Double Buchwald-artwig coupling, Manganese(III) acetate, Microwave In view of our interest in anti-infectious drug discovery, 1 we have recently explored the antileishmaniasis potential of some diamidoximes. everal diamidoximes presenting a,3- dihydrofuran heterocyclic scaffold and obtained via a single Buchwald-artwig coupling reaction (cheme 1) showed interesting antiparasitic activities. artwig amination; 6 while others include an intramolecular domino process, 7 or a double amination on the same aryl halide followed by an intermolecular eck reaction. 8 erein, we report a study allowing a convenient one-pot double Buchwald-artwig coupling reaction using three aminobenzonitriles differing from the cyano position (ortho, meta, or para) and a,3-dihydrofuran derivative bearing two bromine atoms. The combination of these aminobenzonitriles R 1 = Me, Ph R = Bn, Ph These promising results encouraged us to synthesize a series of dicyano-derivatives using various aminobenzonitriles so as to perform a double Buchwald-artwig reaction. ur earlier results had shown that Buchwald-artwig amination realized on the sulfone moiety led to better yields. Thus, we were able to use this difference in reactivity to carry out a onepot double Buchwald-artwig reaction. ince Buchwald-artwig s discovery, the amination reaction has successfully been applied to heteroaryl substrates, such as pyridines, quinolines, thiophenes, thiazoles, indoles, 1,3,5-triazines, or pyrimidines. 3 Moreover, C- crosscoupling reaction on dihalogenated compounds has been fairly thoroughly investigated, as reported in the literature. 4 owever, there have been few examples of efficiently modulating simple aryl scaffolds, particularly with products containing a sulfone moiety. 5 To our knowledge, very few one-pot Buchwad-artwig coupling reactions have been conducted. ne of these is reported as a tandem inter- and intramolecular Buchwald- R 1 R Buchwald-artwig reaction R 1 R.Cl KtBu cheme 1: ynthesis of amidoximes involved in C- cross coupling reactions allowed us to access several dissymmetric dicoupled products. The required starting material, 5-(4-bromophenyl)-4-(4- bromophenylsulfonyl)-,-diphenyl-,3-dihydrofuran (), was synthesized in two steps (see cheme ). Firstly, the - ketosulfone 1 was obtained by using a previously reported microwave irradiated method. 9 In the second step, the - ketosulfone 1 was converted into the desired,3-dihydrofuran derivative under microwave irradiation, via a manganese(iii) acetate-based oxidative cyclization between compound 1 and 1,1-diphenylethene. 10 Thus, we obtained our key-substrate, a double aryl halide (), to be used in conducting the Buchwald-artwig coupling reaction. First of all, the reaction of 5-(4-bromophenyl)-4-(4- bromophenylsulfonyl)-,-diphenyl-,3-dihydrofuran () with -aminobenzonitrile was conducted with only one equivalent of amine. We obtained a mixture of monocoupled 3, 11 dicoupled 4aa, 11 and unreacted products (cheme 3). R 1 R

3 + Cl 1) a 3, ac 3, water, 100 C 00 W, 0 min. ) water, 100 C 00 W, 45 min. 7% 1 C Mn(Ac) 3, Cu(Ac) Ac, 80 C 00 W, 60 min. 5% cheme : ynthesis of 5-(4-bromophenyl)-4-(4-bromophenylsulfonyl)-,-diphenyl-,3-dihydrofuran Pd-catalyst, base, T C., Toluene 3 + 4aa cheme 3: Reaction of in a Buchwald-artwig reaction with -aminobenzonitrile The presence of one monocoupling product (3) revealed a difference in reactivity between the two brominated positions. This difference can be attributed to the electron-attracting effect of the sulfonyl group. Indeed, in the oxidative addition step, Pd(0) acts as a nucleophile and preferentially attacks the most electron-deficient position. 1 The position on which the first coupling reaction took place was confirmed by X-ray diffraction analysis of compound 3 (-{4-[-(4-bromophenyl)- 5,5-diphenyl-4,5-dihydrofuran-3-ylsulfonyl]phenylamino}- benzonitrile, Fig. 1). 13 In order to optimize the one-pot double Buchwald-artwig reaction, we started by investigating the conditions most likely to lead to a majority of monocoupled product in the first step. The study, realized with -aminobenzonitrile, examined various parameters (Table 1). Then, studies to optimize the temperature were undertaken (Entries 1, 7-10). We noted that yields of monocoupled product 3 increased from rt to 70 C, but decreased on reaching 100 C, favoring the dicoupled product. Concerning the equivalent number of amine (Entries 1, 11, 14, 16), it appeared that 1.4 equivalent of amine led to the best yield of monocoupled product. Indeed, we observed some selectivity of monosubstituted product (41% of monocoupled vs 17% of dicoupled product). Moreover, as shown in Table 1, the use of three equivalents of amine led to complete consumption of the starting material, and we obtained, as expected, a majority of double-coupled product 4 (67%). This last result (Entry 16) is considered at the time when the second amine was added. We began with two catalyst systems and different bases (Entries 1-6). We noted that the combined use of Pd(Ac) /BIAP and Cs C 3 appeared to be the best reactive combination. 14

4 Figure 1: RTEP view of compound 3 Table 1: urvey of Buchwald-artwig reaction conditions Entry Amine nbr equivalent Catalyst a Base b Temperature yield c % yield c 3 % yield c 4aa % Pd(Ac) / BIAP Cs C Pd(PPh 3) 4 Cs C Pd(Ac) / BIAP K C Pd(Ac) / BIAP a C Pd(Ac) / BIAP K 3P Pd(Ac) / BIAP KtBu Pd(Ac) / BIAP Cs C 3 r.t Pd(Ac) / BIAP Cs C Pd(Ac) / BIAP Cs C Pd(Ac) / BIAP Cs C Pd(Ac) / BIAP Cs C d 1 Pd(Ac) / BIAP Cs C e 1 Pd(Ac) / BIAP Cs C Pd(Ac) / BIAP Cs C e 1.4 Pd(Ac) / BIAP Cs C Pd(Ac) / BIAP Cs C e 3 Pd(Ac) / BIAP Cs C a 4 mol% b 1. eq. base for 1 eq. amine c Reaction in dry toluene, under argon atmosphere, during 1h, yields for isolated products based on compound d Crown ether in catalytic amount e Crown ether in stoichiometric amount. ext, we explored the compound produced by the sequential double Buchwald-artwig coupling reaction. First, we kept the same catalyst system and the same base, which were the most efficient. Then, in order to maximize double coupling product, we increased the amount of amine and the temperature. The first attempt was performed at 100 C, using 3 equivalents of the second aminobenzonitrile. This second coupling reaction was improved by the use of crown ether. When we tested the influence of crown ether on coupling reactions with the optimized parameters, we observed a significant rate enhancement when stoechiometric amount 18- Crown-6 was added to the reaction mixture (Entries 13, 15, 17). As reported in the literature, crown ether can facilitate the exchange of the halide with amine in the intermediate palladium complex, resulting in the overall reaction rate acceleration. 15 These optimizations enabled us to carry out the one-pot double sequential Buchwald-artwig coupling reaction. We used a combination of three aminobenzonitriles on compound, which permitted us to obtain several dissymmetric dicoupled products (4ab, 4ac, 4ba, 4bc, 4ca, 4cb) (cheme 4, Table ). Moreover, we were able here to synthesize three compounds per reaction at the same time. The method therefore offers great promise for future pharmacomodulation studies.

5 1) ) 1.4 equiv. 3 equiv. Pd(Ac), BIAP, Cs C 3, Toluene, 70 C, 1 h. Pd(Ac), BIAP, Cs C 3, Crown ether Toluene, 100 C, 3 h. 4aa + + 4ab 4bb cheme 4: Reaction of in the one-pot double sequential Buchwald-artwig coupling reaction with -aminobenzonitrile and 3-aminobenzonitrile Table : ynthesis of dicoupled products 16 Entry a First Amine econd Amine 1 Total coupling yield % Dicoupled of 1rst Amine Product/ yield b (%) Dissymmetric Product / Yield b (%) Dicoupled of nd Amine Product/ yield b (%) 83 4aa (31) 4ab (35) 4bb (17) 86 4aa (0) 4ac (3) 4cc( 34) bb (14) 4ba (36) 4aa (1) bb (11) 4bc (1) 4cc (15) 5 7 4cc (16) 4ca (1) 4aa (37) cc (7) 4cb (34) 4bb (6) a 4 mol% Pd (Ac), 4 mol% BIAP,.86 mmol Cs C 3,.35 mmol of first aminobenzonitrile in dry toluene under argon atmosphere at 70 C for 1 h; then, 4 mol% Pd(Ac), 4 mol% BIAP, 6.05 mmol Cs C 3, 5.04 mmol of second aminobenzonitrile, 5.04 mmol crown ether are added at 100 C b yields for isolated products based on compound. In summary, we have developed a novel and efficient method for a one-pot sequential double Buchwald-artwig coupling reaction on,3-dihydrofuran derivatives. We show that by controlling the amount of amine and the temperature, it is possible to synthesize dissymmetric dicoupled products with rather good global coupling yields. This strategy can now be exploited with various amines, allowing access to a wide range of dihydrofuran derivatives. It should contribute to a combinatorial chemistry approach, of value in pharmacomodulation studies. Acknowledgments This work was supported by the Centre ational de le Recherche cientifique and the Université de la Méditerranée. We would like to express our thanks to Dr V. Remusat for RM spectra recording. References and notes 1 (a) Kabri, Y.; Azas,.; Dumètre, A.; utter,.; Laget, M.; Verhaeghe, P.; Gellis, A.; Vanelle, P. Eur. J. Med. Chem. 010, 45, 616-6; (b) Juspin, T.; Laget, M.; Terme, T.; Azas,.; Vanelle, P. Eur. J. Med. Chem. 010, 45, ; (c) Crozet, M. D.; Botta, C.; Gasquet, M.; Curti, C.; Remusat, V.; utter,.; Chapelle.; Azas,.; De Meo, M.; Vanelle, P. Eur. J. Med. Chem. 009, 44, ; (d) Verhaeghe, P.; Azas,.; Gasquet, M.; utter,.; Ducros, C.; Laget, M.; Rault,.; Rathelot, P.; Vanelle, P. Bioorg. Med. Chem. Lett. 008, 18, ; (e) Upcroft, J. A.; Dunn, L. A.; Wright, J. M.; Benakli, K.; Upcroft, P.; Vanelle, P. Antimicrob. Agents Chemother. 006, 50, ; (f) Rathelot, P.; Azas,.; El-Kashef,.; Delmas, F.; Di Giorgio, C.; Timon-David, P.; Maldonado, J.; Vanelle, P. Eur. J. Med. Chem. 00, 37, ; (g) Vanelle, P.; Meuche, J.; Maldonado, J.; Crozet, M. P.; Delmas, F.; Timon- David, P. Eur. J. Med. Chem. 000, 35, ; (h) Upcroft, J. A.; Campbell, R. W.; Benakli, K.; Uocroft, P.; Vanelle, P. Antimicrob. Agents Chemother. 1999, 43, 73-76; (i) Delmas, F.; Gasquet, M.; Timon-David, P.; Madadi,.; Vanelle, P.; Vaille, A.; Maldonado, J. Eur. J. Med. Chem. 1993, 8, 3-7; (j) Jentzer,.; Vanelle, P.; Crozet, M. P.; Maldonado, J.; Barreau, M. Eur. J. Med. Chem. 1991, 6, Bouhlel, A.; Curti, C.; Dumètre, A.; Laget, M.; Crozet, M. D.; Azas,.; Vanelle, P. Bioorg. Med. Chem. 010, 18, (a) Das, A. R.; Medda, A.; ingha, R. Tetrahedron Lett. 010, 51, ; (b) Patriciu, -I.; Fînaru, A-L.; Massip,.; Léger, J-M.; Jarry, C.; Guillaumet, G. Eur. J. rg. Chem. 009,, ; (c) Begouin, A.; esse,.; Queiroz, M-J. R. P.; Kirsch, G. Eur. J. rg. Chem. 007, 10, ; (d) Queiroz, M-J. R. P.; Calhelha, R. C.; Kirsch, G. Tetrahedron 007, 63, ; (e) ostyn,.; Maes, B. U. W.; Van Baelen, G.; Gulevskaya, A.; Meyers, C.; mits, K. Tetrahedron 006, 6, 4684; (f) ing Li, C.; Dixon, D. D. Tetrahedron Lett. 004, 45, (a) Koley, M.; chnuerch, M.; Mihovilovic, M. D. ynlett 010, 10, ; (b) Romero, M.; arrak, Y.; Basset, J.; rue, J. A.; Pujol, M.

6 D. Tetrahedron 009, 65, ; (c) Wagaw,.; Buchwald,. L. J. rg. Chem. 1996, 61, (a) Cao, J.; Fine, R.; Gritzen, C.; ood, J.; Kang, X.; Klebansky, B.; Lohse, D.; Mak, C. C.; McPherson, A.; oronha, G.; Palanki, M...; Pathak, V. P.; Renick, J.; oll, R.; Zeng, B.; Zhu,. Bioorg. Med. Chem. Lett. 007, 17, ; (b) Cao, J.; oll, R. M.; oronha, G.; Barrett, K.; Gritzen, C.; ood, J.; Mak, C. C.; Mc Pherson, A.; Pathak, V. P.; Renick, J.; plittgerber, U.; Zeng, B. PCT Int. Appl., , Loones, K. T. J.; Maes, B. U. W.; Dommisse, R. A.; Lemière, G. L. F. Chem. Commun., 004, Cuny, G.; Bois-Choussy, M.; Zhu, J. Angew. Chem. Int. Ed. 003, 4, andakumar, M..; Verkade, J. G. Angew. Chem. Int. Ed. 005, 44, For procedure see : (a) Cohen, A.; Crozet, M. D.; Rathelot, P.; Vanelle, P. Green Chem. 009, 11, ; (b) Curti, C.; Laget, M.; rtiz Carle, A.; Gellis, A.; Vanelle, P. Eur. J. Med. Chem. 007, 4, (4- bromophenyl)--(4-bromophenylsulfonyl)ethanone (1) (with 00W, and 45 min. in the nd step): white solid, mp 16 C. 1 MR (DM-d6, 00 Mz): 5.4 (s,, C ), 7.74 (d,, C, J = 8.6 z), (m, 6, C ). 13 C MR (DM-d6, 50 Mz): 6.3 (C ), 18.5 (C), 18.8 (C), (C), (C), 13.1 (C), 13.5 (C), (C), (C), (C). Anal. Calcd for C : C, 40.;,.41. Found: C, 40.45;, For procedure see: Curti. C.; Crozet, M. D.; Vanelle, P. Tetrahedron 009, 65, (4-bromophenyl)-4-(4-bromophenylsulfonyl)-,- diphenyl-,3-dihydrofuran (): white solid, mp 166 C. 1 MR (CDCl 3, 00 Mz): 3.76 (s,, C ), 7.9 (s, 10, 10C), 7.50 (s, 4, 4C), 7.57 (d,, C, J = 8.7 z), 7.67 (d,, C, J = 8.7 z). 13 C MR (CDCl 3, 50 Mz): 45.3 (C ), 9.1 (C), (C), (C), 15.5 (4C), 16.1 (C), 16.9 (C), 18.1 (C), 18.4 (C), 18.6 (4C), (4C), 13.3 (C), (C), (C), (C). Anal. Calcd for C 8 0 3: C, 56.39;, Found: C, 56.36;, General procedure for the first step optimization: Into a two-necked flask containing 5 ml of dry and degazed toluene, under inert atmosphere were added compound (0.5 g, 0.84 mmol), -aminobenezonitrile (0.139 g, 1.18 mmol), palladium acetate (0.007 g, 0.03 mmol), BIAP (0.01 g, 0.03 mmol), and cesium carbonate (0.75 g, 1.43 mmol). The reaction mixture was stirred at 70 C from 1h, and monitored by TLC. olvent evaporation gave a crude mixture which was solubilized in dichloromethane and filtered through Celite in order to remove inorganic salts. The mixture was purified by column chromatography (Chloroform/ Petrolum Ether/DiethyEther: 5/4.5/0.5) and products obtained were recrystallized from isopropanol. -{4-[-(4-bromophenyl)-5,5-diphenyl-4,5-dihydro-furan-3-ylsulfonyl]- phenylamino}benzonitrile (3): white solid, mp 171 C. 1 MR (CDCl 3, 00 Mz): 3.81 (s,, C ), 6.46 (bs, 1, 1), (m, 3, 3C), (m, 10, 10C), 7.37 (s, 1, C), (m, 1, C), (m, 5, 5C), (m,, C). 13 C MR (CDCl 3, 50 Mz): 45.6 (C ), 91.8 (C), 10. (C), (C), (C), (C), (C), 1. (C), 15.5 (4C), 15.8 (C), 17. (C), 18.0 (C), 18.5 (4C), 19.0 (C), 131. (C), (C), (C), (C), (C), (C), 144. (C), 145. (C), (C). Anal. Calcd for C : C, 66.35;, 3.98;, 4.4. Found: C, 66.7;, 4.16;, (4-{-[4-(-cyanophenylamino)phenyl]-5,5-diphenyl-4,5-dihydrofuran- 3-ylsulfonyl}phenyl-amino)benzonitrile (4aa): white solid, mp 0 C. 1 MR (CDCl 3, 00 Mz): 3.8 (s,, C ), 6.45 (bs, 1, 1), 6.48 (bs, 1, 1), (m, 4, 4C), 7.18 (d,, C, J = 8.6 z), (m, 10, 10C), (m, 8, 8C), 7.86 (d,, C, J = 8.6 z). 13 C MR (CDCl 3, 50 Mz): 45.7 (C ), 91. (C), (C), 10.0 (C), (C), (C), (C), 117. (C), (C), (C), (C), 11.0 (C), 1.1 (C), 1.5 (C), 15.6 (4C), 17.9 (C), 18.5 (4C), 18.9 (C), (C), (C), (C), (C), (C), (C), 143. (C), (C), (C), (C), 145. (C), (C). MR (EI): m/z calcd for C M+ + : Found: chröter,.; tock, C.; Bach, T. Tetrahedron 005, 61, Crystal data for compound 3: C , colourless prism (0.4x0.x0. mm 3 ), M W = , orthorhombic, space group Pna1 (T = 93 K), a = () Å, b = () Å, c = (5) Å, = 90 = 90, 90 V = (10) Å 3, Z = 4, D calcd = g.cm -1, = mm -1, F(000) = 1336, index ranges 0 h 15, 0 k 1, -30 l 0, range = , 388 variables and 1 restraint, were refined for 76 reflections with l l to R = 0.05, GoF = Crystallographic data for the structure 3 have been deposited with the Cambridge Crystallographic Data Centre (CCDC) under number Copie of the data can be obtained, free of charge, on application to CCDC, 1 Union Road, Cambridge CB 1EZ, UK (fax: +44 (0) or e- mail: deposit@ccdc.cam.ac.uk). 14 (a) cholz, U.; chlummer, B. Tetrahedron, 005, 61, ; (b) Wolfe, J. P.; Buchwald,. L. J. rg. Chem. 000, 65, ; (c) cholz, U.; Wolfe, J. P.; Wagaw,.; Buchwald,. L. J. Am. Chem. oc. 1996, 118, (a) Torisawa, Y.; ishi, T.; Minamikawa, J-I. Bioorg. Med. Chem. Lett. 000, 10, (b) Wolfe, J. P.; Wagaw,.; Marcoux, J-F.; Buchwald,. L. Acc. Chem. Res. 1998, 31, General procedure for one pot double sequential Buchwald-artwig coupling reaction: into a two-necked flask containing 50 ml of dry and degazed toluene, under inert atmosphere were added compound (1 g, 1.68 mmol), corresponding first aminobenezonitrile (0.78 g,.35 mmol), palladium acetate (0.015 g, 0.07 mmol), BIAP (0.04 g, 0.07 mmol), and cesium carbonate (0.55 g,.86 mmol). The reaction mixture was stirred at 70 C from 1h. Then were added the second aminobenzonitrile (0.595 g, 5.04 mmol), crown ether (1.33 g, 5.04 mmol), palladium acetate (0.015 g, 0.07 mmol), BIAP (0.04 g, 0.07 mmol), and cesium carbonate (1.17 g, 6.05 mmol). The reaction mixture was stirred at 100 C from 3h, and monitored by TLC. olvent evaporation gave a crude mixture which was solubilized in dichloromethane and filtered through Celite in order to remove inorganic salts. The mixture was purified by column chromatography (Dichloromethane/Petrolum Ether/DiethyEther: 6.5/3/0.5) and products obtained were recrystallized from isopropanol. 3-(4-{-[4-(3-cyanophenylamino)phenyl]-5,5-diphenyl-4,5-dihydrofuran- 3-ylsulfonyl}phenylamino)benzonitrile (4bb): white solid, mp 188 C. 1 MR (DM-d6, 00 Mz): 3.78 (s,, C ), 7.10 (d,, C, J = 8.8 z), 7.0 (d,, C, J = 8.7 z), (m, 9, 9C), (m, 9, 9C), 7.58 (d,, C, J = 8.8 z), 7.8 (d,, C, J = 8.7 z), 9.04 (s, 1, 1), 9.13 (s, 1, 1). 13 C MR (DM-d6, 50 Mz): 45.3 (C ), 90. (C), (C), 11. (C), (3C), (C), (C), 119. (C), (C), 10.9 (C), 1.3 (C), 13. (C), 14.1 (C), 15.0 (C), 15.1 (4C), 17.6 (C), 18.5 (5C), (C), (C), (C), (C), 14. (C), (C), (C), (C), (C), (C). MR (EI): m/z calcd for C M+ + : Found: (4-{-[4-(4-cyanophenylamino)phenyl]-5,5-diphenyl-4,5-dihydrofuran- 3-ylsulfonyl}phenylamino)benzonitrile (4cc): white solid, mp 09 C. 1 MR (DM-d6, 00 Mz): 3.80 (s,, C ), (m, 10, 10C), (m, 3, 3C), (m, 4, 4C), (m, 7, 7C), (m,, C), 9.3 (s, 1, 1), 9.39 (s, 1, 1). 13 C MR (DM-d6, 50 Mz): 45.3 (C ), 90.7 (C), (C), 10.0 (C), (C), (C), 117. (C), (4C), (C), (C), 10.5 (C), 15.3 (4C), 17.9 (C), 18.6 (C), 18.7 (4C), 131. (C), 13.7 (C), (4C), (C), 144. (C), (C), (C), (C), (C). MR (EI): m/z calcd for C M+ + : Found: (4-{-[4-(3-cyanophenylamino)phenyl]-5,5-diphenyl-4,5-dihydrofuran- 3-ylsulfonyl}phenylamino)benzonitrile (4ab): white solid, mp 0 C. 1 MR (DM-d6, 00 Mz): 3.78 (s,, C ), 7.03 (d,, C, J = 8.7 z), (m, 3, 3C), (m, 8, 8C), (m, 8, 8C), 7.57 (d,, C, J = 8.8 z), (m, 3, 3C), 9.04 (s, 1, 1), 9.1 (s, 1, 1). 13 C MR (DM-d6, 50 Mz): 45.4 (C ), 90.4 (C), (C), (C), 11.3 (C), (C), (C), (C), (C), (C), 10.1 (C), 11.9 (C), 1.5 (C), 13.8 (C), 14.3 (C), 15.3 (4C), 17.3 (C), 17.8 (C), 18.5 (C), 18.7 (4C), (C), (C), (C), (C), (C), 144. (C), (C), 145. (C), (C), (C). MR (EI): m/z calcd for C M+ + : Found: (4-{-[4-(4-cyanophenylamino)phenyl]-5,5-diphenyl-4,5-dihydrofuran- 3-ylsulfonyl}phenylamino)benzonitrile (4ac): yellow solid, mp 138 C. 1 MR (DM-d6, 00 Mz): 3.79 (s,, C ), (m, 3, 3C), (m, 10, 10C), (m, 5, 5C), (m, 5, 5C), (m, 3, 3C), 9.1 (s, 1, 1), 9.31 (s, 1, 1). 13 C MR (DM-d6, 50 Mz): 45.4 (C ), 90.6 (C), (C), (C), (C), (C), (C), (C), 117. (C), (C), (C), 10.6 (C), 1.0 (C), 13.8 (C), 15.3 (4C), 17.8 (C), 18.7 (4C), 131. (C), (C), (C), (C), (C), (C), 144. (C), (C), (C), (C), (C). MR (EI): m/z calcd for C M+ + : Found: (4-{3-[4-(3-cyanophenylamino)phenyl]-5,5-diphenyl-4,5-dihydrofuran- -ylsulfo-nyl}phenylamino)benzonitrile (4ba): yellow solid, mp 11 C. 1 MR (DM-d6, 00 Mz): 3.78 (s,, C ), (m, 5, 5C), (m, 18, 18C), (m, 3, 3C), 8.98 (s, 1,

7 1), 9.13 (s, 1, 1). 13 C MR (DM-d6, 50 Mz): 45.4 (C ), 90.4 (C), (C), (C), 11.4 (C), (C), (C), (C), (C), (C), (C), 10.8 (C), 11.1 (C), 1.9 (C), 13.5 (C), 15.3 (4C), 17.8 (C), 18.7 (4C), (C), (C), (C), (C), (C), (C), 14.4 (C), (C), (C), (C), (C), (C). MR (EI): m/z calcd for C M+ + : Found: (4-{-[4-(4-cyanophenylamino)phenyl]-5,5-diphenyl-4,5-dihydrofuran- 3-ylsulfonyl}phenylamino)benzonitrile (4bc): yellow solid, mp 11 C. 1 MR (DM-d6, 00 Mz): 3.79 (s,, C ), 7.10 (d,, C, J = 8.7 z), (m, 11, 11C), (m, 7, 7C), 7.58 (d,, C, J = 8.7z), 7.67 (d,, C, J = 8.7 z), 7.8 (d,, C, J = 8.7z), 9.14 (s, 1, 1), 9.3 (s, 1, 1). 13 C MR (DM-d6, 50 Mz): 45.4 (C ), 90.6 (C), (C), (C), 11.4 (C), (C), (C), 117. (C), (C), (C), (C), 10.6 (C), 11.1 (C), 13.5 (C), 15.3 (4C), 17.3 (C), 17.9 (C), 18.7 (4C), (C), 131. (C), (C), (C), 14.4 (C), (C), (C), (C), (C), (C). ). MR (EI): m/z calcd for C M+ + : Found: (4-{3-[4-(4-cyanophenylamino)phenyl]-5,5-diphenyl-4,5-dihydrofuran- -ylsulfonyl}phenylamino)benzonitrile (4ca): yellow solid, mp 140 C. 1 MR (DM-d6, 00 Mz): 3.79 (s,, C ), (m, 1, 1C), (m,, C), (m, 5, 5C), (m, 6, 6C), (m, 5, 5C), (m, 5, 5C), (m,, C), 8.98 (s, 1, 1), 9.39 (s, 1, 1). 13 C MR (DM-d6, 50 Mz): 45.4 (C ), 90.6 (C), 10.0 (C), (C), (C), (C), (C), (C), 117. (C), (C), (C), 10.8 (C), 1.9 (C), 15.3 (4C), 17.9 (C), 18.6 (C), 18.7 (4C), 131. (C), 13.9 (C), (C), (C), (C), (C), (C), (C), (C), 146. (C), 160. (C). MR (EI): m/z calcd for C M+ + : Found: (4-{3-[4-(4-cyanophenylamino)phenyl]-5,5-diphenyl-4,5-dihydrofuran- -ylsulfonyl}phenylamino)benzonitrile (4cb): yellow solid, mp 139 C. 1 MR (DM-d6, 00 Mz): 3.79 (s,, C ), (m, 6, 6C), (m, 6, 6C), (m, 8, 8C), (m, 4, 4C), (m,, C), 9.13 (s, 1, 1), 9.39 (s, 1, 1). 13 C MR (DM-d6, 50 Mz): 45.4 (C ), 90.5 (C), 10.0 (C), (C), 11.4 (C), (C), (C), 117. (C), (C), 10.1 (C), 11.1 (C), 1.5 (C), 13.4 (C), 14.3 (C), 15.3 (4C), 17.8 (C), 18.7 (4C), (C), 131. (C), (C), 13.9 (C), (C), 14.4 (C), (C), (C), (C), 146. (C), (C). MR (EI): m/z calcd for C M+ + : Found: