N-Bromosuccinimide was found to efficiently catalyze the synthesis of highly functionalized, tetra-substituted furan derivatives in the one-pot reactions of but-2-ene-1,4-diones and acetoacetate esters in the presence of i-PrOH as solvent under mild and neutral conditions at 80–90 °C for 3–7 h in high yields (87–94 %)

FARHAD RAMZANIAN-LEHMALI

HASSAN GHASEMNEJAD–BOSRA

MOHAMMAD FARAJE

SETAREH HABIBZADEH

Journal of the Serbian Chemical Society

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  J. Serb. Chem. Soc. 75 (3) 299–305 (2010) UDC 547.461.4+547.223+66.091+544.4:547.72 JSCS–3961 Original scientific paper doi: 10.2298/JSC090824025G 299 An efficient one-pot synthesis of highly substituted furans catalyzed by N-bromosuccinimide HASSAN GHASEMNEJAD–BOSRA1*, MOHAMMAD FARAJE1, SETAREH HABIBZADEH2 and FARHAD RAMZANIAN-LEHMALI3 1Islamic Azad University-Babol Branch, School of Science, P.O. Box 755, Babol, 2Industrial Noshiravani University, Babol and 3University of Payamenoor, Babol, Iran (Received 24 August, revised 25 December 2009) Abstract: N-Bromosuccinimide was found to  efficiently catalyze the sy nthesis of highly  functionalized, tetra- substituted fura n derivative s in  the one-pot re -actions of but-2-ene-1,4-diones and acetoacetate esters in the presence of i-PrOH as solvent u nder mild and neutral conditi ons at 8 0–90 °C f or 3–7 h in  hi gh yields (87–94 %). Keywords: hig hly substitut ed furans; N-bromosuccinimide; but-2-ene-1,4-di-ones; acetoacetate esters. INTRODUCTION Highly substi tuted furans are a structural co mponent of a vast number of biologically active natural and s ynthetic co mpounds.1–4 These com pounds ar e found as stru ctural units i n many natural products, s uch as kallolides, 5 combra-nolides,6 pheromones7 and polyether antibiotics.8 These heterocycles have found applications in many pharmaceuticals, fragrances and dyes.9 Furan subunits have also been used as building blocks for a large number of heterocyclic compounds and as s ynthons in natural product synthesis.10 As a consequence, the s ynthesis of furan derivatives has been a subject of research  for over a century, and a variety of well-established classical methods are now available in the litera tu-re.11–14 The development of newer approaches for heterocy cle syntheses e m-ploying efficient and econom ic routes i s a popular resear ch area nowadays. The most common strategy involved in the s ynthesis of furans is  the cyclization15 of 1,4-dicarbonyl com pounds. Of the othe r various m ethods, s yntheses involving transition-metal salts have  recently  bee n described for the preparation of sub-stituted furan derivatives. 16,17 Oh et al.18 sy nthesized highly subs tituted furans via Pt-catalyzed hy droxyl- or alkoxy-assist ed cy clization of 2-(1-alkynyl)-2-al-kene-1-ones. More recen tly, Dey  and coworkers r eported a novel method t o                                                                                                                     * Corresponding author. E-mail: h_ghasem2000@yahoo.it 2010 Copyright (CC) SCS___________________________________________________________________________________________________________________________Available online at www.shd.org.rs/JSCS/300 GHAS EMNEJAD-BOSRA et al. highly su bstituted furans b y I nCl3-catalyzed nucleophilic  addition followed by  cyclization reaction, although it is limited to specific substrate classes.19 EXPERIMENTAL The employed chemicals were obtained from either Merck or Fluka. The IR spectra were recorded using a Shimadzu 435-U-04 spectrophotometer (KBr pellets) and the NMR spectra were obtaine d in CD Cl3 using  a 90 MH z JE OL FT NMR spectrometer. Al l melting point s were determined on a Büchi 530 melting point apparatus and are reported uncorrected. Typical procedure for the synthesis of tetra-substituted furans  To a stirred sol ution of but-2-ene-1,4-dione, 1a (0.24 g, 1.0 mmol), and methyl aceto-acetate, 2a (0.18 g, 1.0 m mol), in dry  i-PrOH (7.0 ml) was added anhydrous N-bromosucci-nimide, NBS (52 mg, 0.23 mmol). The reaction mixture was then stirred und er reflux at 80– –90 °C for 3.1 h. After co mplete disappearance of the startin g materials (monitored by TLC using petroleum ether–chloroform (6:4)), the  solvent was removed from the reaction mixture on a rot ary evaporator. The re sidue was then diluted  with water (15 ml) and extracted with CHCl3 (4×15 m l). The organ ic lay er was se parated, washe d with brine an d then dried ov er anhydrous Mg SO4. Re moval of the solvent r esulted in a  sol id which  wa s c hromatographed over silica gel using petroleum ether and an increasing proportion of ethy l acetate as eluent. Petroleum ether–ethyl acetate (96:4) eluent gave a solid which was recrystallized from chloro-form–petroleum ether (2:8): 3a (0.31 g, 93 %). white solid, m.p. 92 °C. The product s 3b–j were  obtained in  a similar manner using the appropriate but-2-ene-  -1,4-dione and acetoacetate ester. The product s were chara cterized on t he ba sis of their phy sical and spectral analy sis (Table I) and by direct comparison with literature data.19 TABLE I. IR (KBr), 1H-NMR and 13C-NMR spectral data of the tetra-substituted furans 3a–j Product IR, ν~ / cm-1 1H-NMR, δ / ppm 13C-NMR, δ / ppm 3a 3068, 1712, 1610, 1452, 1058, 772 2.35 (3H, s, –CH3), 3.28 (3H, s, –OCH3), 4.45 (2H, s,  –CH2–) , 7.36–7.55 (10H, m, Ar,) 14.40 (–CH3), 35.63 (–CH2–), 51.12 (–OCH3), 107.69 (C3), 122.79 (C4), 126.01–134.57 (Ph), 149.02 (C5), 155.15 (C2), 166.78 (–CO2Me), 196.69 (CO) 3b 3063, 1716, 1625, 1460, 1050, 796 1.24 (3H, t, –CH2–CH3), 2.34 (3H, s, –CH3), 4.12 (2H, q, –CH2–CH3), 4.42 (2H, s, –CH2–), 7.30–7.57 (10H, m, Ar) 14.01 (–CH2–CH3), 16.49 (–CH3), 37.57 (–CH2–), 59.74 (–OCH2–), 111.32 (C3), 125.65 (C4), 127.97–135.12 (Ph) 149.02 (C5), 155.74 (C2), 166.49 (–CO2Et), 196.62 (CO) 3c 3058, 2933, 1783, 1678, 1509, 1316, 1050, 827 2.31 (3H, s, –CH3), 2.35 (3H, s, –CH3), 2.44 (3H, s,–CH3), 3.62 (3H, s, –OCH3), 4.43 (2H, s, –CH2–), 7.18–7.33 (4H, dd, Ar), 7.35 (2H, d, Ar), 7.96 (2H, d, Ar) 14.85 (–CH3), 21.08 (–CH3), 21.67 (–CH3), 35.78 (–CH2–), 51.38 (–OCH3) 114.36 (C3), 114.85 (C4), 127.03–144.15 (Ph), 150.79 (C5), 159.27 (C2), 165.08 (–CO2Me), 197.33 (CO)   2010 Copyright (CC) SCS___________________________________________________________________________________________________________________________Available online at www.shd.org.rs/JSCS/ ONE-POT SYNTHESIS OF HIGHLY SUBSTITUTED FURANS 301 TABLE I. Continued Product IR, ν~ / cm-1 1H-NMR, δ / ppm 13C-NMR, δ / ppm 3d 3070, 1710, 1609, 1448, 1250, 1108, 770 1.22 (3H, t, –CH2–CH3), 2.32 (3H, s, –CH3), 2.34 (3H, s, –CH3), 2.37 (3H, s,–CH3), 4.10 (2H, q, –CH2–CH3), 4.45 (2H, s, –CH2–), 7.03–7.19 (4H, dd, Ar), 7.76 (2H, d, Ar), 8.02 (2H, d, Ar)14.15 (–CH2–CH3), 16.58 (–CH3), 21.10 (–CH3), 21.82 (–CH3), 35.79 (–CH2–), 58.45 (–OCH2–), 115.01 (C3), 114.97 (C4) 127.03–143.47 (Ph), 157.98 (C5), 164.35 (C2), 166.08 (–CO2Et), 197.97 (CO) 3e 3080, 1704, 1605, 1442, 1238, 1025, 785 2.36 (3H, s, –CH3), 3.30 (3H, s, –OCH3), 4.47 (2H, s, –CH2–), 7.48–7.56 (4H, dd, Ar), 7.70–7.81 (4H, dd, Ar) 15.32 (–CH3), 31.29 (–CH2–), 50.73 (–OCH3), 118.49 (C3), 123.84 (C4), 126.03–141.49 (Ph), 149.02 (C5), 155.17 (C2), 165.23 (–CO2Me), 196.70 (CO) 3f 3085, 1709, 1611, 1437, 1245, 1062, 788 1.24 (3H, t, CH2–CH3), 2.41 (3H, s, –CH3), 4.13 (2H, q,–CH2–CH3), 4.48 (2H, s, –CH2–), 7.41–7.50 (4H dd, Ar), 7.68–7.76 (4H, dd, Ar)16.01 (CH2–CH3), 17.07 (–CH3), 36.11 (–CH2–), 59.82 (–OCH2–), 116.12 (C3), 116.97 (C4), 131.17–147.53 (Ph), 158.38 (C5), 165.25 (C2) , 165.98 (–CO2Et), 198.17 (CO) 3g 3100, 1705, 1610, 1450, 1248, 1055, 792 2.35 (3H, s, –CH3), 3.28 (3H, s, –OCH3), 4.45 (2H, s, –CH2–), 7.39 (2H, d, Ar), 7.50–7.58 (4H, dd, Ar), 7.85 (2H, d, Ar) 14.68 (–CH3), 31.57 (–CH2–), 51.38 (–OCH3), 116.33 (C3), 127.81 (C4), 129.10–142.40 (Ph), 151.03 (C5), 156.37 (C2), 167.03 (–CO2Me), 196.19 (CO) 3h 3090, 1706, 1613, 1458, 1090, 838 1.20 (3H, t, –CH2–CH3), 2.32 (3H, s, –CH3,), 4.08 (2H, q, –CH2–CH3), 4.51 (2H, s, –CH2–), 7.31 (2H, d, Ar), 7.45–7.51 (4H, dd, Ar), 7.73 (2H, d, Ar) 15.01 (–CH2–CH3), 17.19 (–CH3), 34.24 (–CH2–), 59.01 (–OCH2–), 116.57 (C3), 115.87 (C4), 132.54–147.78 (Ph), 157.44 (C5), 166.05 (C2), 167.01 (–CO2Et), 197.18 (CO) 3i 3110, 1703, 1606, 1451, 1100, 840 2.18 (3H, s, –CH3), 2.21 (3H, s, –CH3), 2.29 (3H, s, –CH3), 3.32 (3H, s, –OCH3,), 4.56 (2H, s, –CH2–) 7.24 (3H, m, Ar), 7.51 (3H, m, Ar) 14.11 (–CH3), 25.98 (–CH3), 26.29 (–CH3), 37.12 (–CH2–), 51.74 (–OCH3) 116.30 (C3), 116.84 (C4), 129.14–145.35 (Ph), 159.70 (C5), 169.47 (C2), 170.22 (–CO2Me), 198.35 (CO) 3j 3105, 1707, 1611, 1452, 1235, 1039, 770 1.23 (3H, t, CH2–CH3), 2.17 (3H, s, –CH3), 2.28 (3H, s,–CH3), 2.31 (3H s, –CH3), 4.10 (2H q, –CH2–CH3), 4.53 (2H, s, –CH2–), 7.12 (3H, m, Ar), 7.49 (3H, m, Ar) 14.15 (–CH2–CH3), 16.58 (–CH3) 26.78 (–CH3), 27.27 (–CH3), 37.48 (–CH2–), 59.37 (–OCH2–), 115.01 (C3), 116.13 (C4) 130.12–145.25 (Ph), 160.15 (C5), 170.31 (C2), 172.15 (–CO2Et), 198.54 (CO) RESULTS AND DISCUSSION In continuation of on-going research o n various tr ansformations by haloge-nating agents  and s ydnones,20–26 and also in order to avoid the drawbacks ge-nerally resulting from  the  use of stron g acidic media in nitrosation reactions, herein is rep orted the use of NBS as a more robust and efficient cataly st in the 2010 Copyright (CC) SCS___________________________________________________________________________________________________________________________Available online at www.shd.org.rs/JSCS/302 GHAS EMNEJAD-BOSRA et al. one-pot synthesis of the highl y functionalized tetra-substituted fur an derivatives 3a–j by reaction of but-2-ene-1,4-diones 1a–e and acetoacetate esters 2a or 2b in i-PrOH in satisfactory  yields (87–94 %) under neutral conditions (Scheme 1, Table II). As shown in Table II, the reac tions occurred satisfactoril y within 3.1– –6.1 h u nder reflux cond itions. The ex perimental results indicate that the m ost effective conversion occurred when a 1:0. 23 substrate:NBS mole ratio was used. Longer reaction tim es were required when lower am ounts of NBS were employed. It is important to note that n o furan deriv atives were afforded when  the reactions were performed in the absence of NBS in the reaction mixture.  Scheme 1. Proposed mechanism for the synthesis of highly substituted furans.26 TABLE II. NBS-catalyzed synthesis of furans 3a–j Entry Product a Ar R Time, h Yield, %b M .p., °C 1 3a C6H5 Me  3.1 93 92 2 3b C6H5 Et 3.9 91 89 3 3c 4-Me-C6H4 Me  4.0 89 83 4 3d 4-Me-C6H4 Et 3.8 87 80 5 3e 4-Br-C6H4 Me  3.3 89 87 6 3f 4-Br-C6H4 Et 5.2 94 85 7 3g 4-Cl-C6H4 Me  4.7 90 96 8 3h 4-Cl-C6H4 Et 5.5 91 94 9 3i 3-Cl,4-Me-C6H3 Me  6.0 93 79 10 3j 3-Cl,4-Me-C6H3 Et 6.1 94 77 aAll the isolated products wer e char acterized by  their  phy sical pr operties, by  1H-NMR, 13C-NMR and IR  spectra and by direct comparison with literature data;19 bisolated yields The mechanism shown in Sche me 2 is proposed for these reactions.26 Thus, t he 1,4-diarylbut-2-ene-1,4-diones act as Michael acceptors and the acetoacetates as nucleophiles resulting in a Michael adduct that under the influence of NBS forms a hemiketal, which undergoes spontaneous dehydration to afford the furans. It is important to note that no furan derivatives were formed when the reactions w ere performed in the presence of HBr as cat alyst. Furthermore, no reaction was see n when the 1,4-diary lbut-2-ene-1,4-diones and acetoacetates were used separ ately as substrates with NBS as the catalyst in the presence of i-PrOH under reflux. The advantages or the char acteristic aspects of the method described in this paper in comparison with other previou sly reported ones are the following: the yields of products were b etter than the pr evious reported yields and in addition, the catalyst NBS in co mparison with 1,3-dibromo-5,5-dimethylhydantoin (DBH) 2010 Copyright (CC) SCS___________________________________________________________________________________________________________________________Available online at www.shd.org.rs/JSCS/ ONE-POT SYNTHESIS OF HIGHLY SUBSTITUTED FURANS 303 and InCl3 is inexpensive, has no moisture sensitivity, and no special measures are required for the reaction.  Scheme 2. The role of the solvent w as also inv estigated. Among the various solvents  tested, i-PrOH afforded the maximum yield of the furan derivative 3a (Table III). It is well known that reactions of this type are m ore efficient in polar solvents,  which was corroborated i n this study  (Table III). It was also observed that t he inclusion of water had very little or no effect on this reaction. TABLE III. Role of the solvent in the synthesis of furan 3a Solvent Ti me,a h Isolated yield of 3a, % i-PrOH 3.0 93 i-PrOH–H2O (6:4) 11 60 MeOH 9.0 52 CH3CN 18 44 CH2Cl2 15 38 THF 14 61 aExtension of the reaction did not improve the product yield 2010 Copyright (CC) SCS___________________________________________________________________________________________________________________________Available online at www.shd.org.rs/JSCS/304 GHAS EMNEJAD-BOSRA et al. CONCLUSIONS The present methodology shows that  N-bromosuccinimide (NBS) is an effi-cient cataly st in t he one-pot s ynthesis of hi ghly functionalized tetra-substituted furan derivatives. The main advantages of the presented protocol a re mild, clean and environmentally benign reaction cond itions, as well as the high yields. Fur-thermore, this method is also expected  to find appli cation in org anic sy nthesis due to the low cost of the reagent. It is believed that this method will be a useful addition to modern synthetic methodologies. Acknowledgements. W e wish to thank the Isla mic Azad  University –Babol Branch , Babol, Iran, for financial support during the realization of this research. И З В О Д  ЕФИКАСНА СИНТЕЗА У ЈЕДНОМ СУДУ ВИСОКО СУПСТИТУИСАНИХ ФУРАНА КАТАЛИЗОВАНА N-БРОМСУКЦИНИМИДОМ HASSAN GHASEMNEJAD-BOSRA1, MOHAMMAD FARAJE1, SETAREH HABIBZADEH2 и FARHAD RAMZANIAN-LEHMALI3 1Islamic Azad University-Babol Branch, School of Science, P.O. Box 755, Babol, 2Industrial Noshiravani University, Babol и 3University of Payamenoor, Babol, Iran Утврђено је да N-бромсукцинимид ефикасно катализује синтезу високо функционали-зованих, тетрасупституисаних деривата фурана у реакцији у једном суду бут-2-ен-1,4-диона и ацатоацетатних естара у i-PrOH као растварачу под благим и неутралним условима на 80– –90 °С током 3–7 h уз високе приносе (87–94 %). (Примљено 24. августа, ревидирано 25. децембра 2009) REFERENCES 1. a) Y. Guindon, M. Therien, Y. Girard, C. Yoakim, J. Org. Chem. 52 (1987) 1680; b) D. J. Goldsmith, E. Kennedy, R. J. Ca mpbell, J. Org. Chem. 40 (1975) 3571; c) B. H. Lip-shutz, Chem. Rev. 86 (1986) 795 2. K. S. Huang, J. Chin. Chem. Soc. 51 (2004) 1305 3. S. Soluj ić, S. S ukdolak, N, Vu ković, N. Niciforovi ć, S. Stani ć, J. Serb. Chem. Soc. 73 (2008) 1039 4. T. Shah, V. Desi, J. Serb. Chem. Soc. 72 (2007) 443 5. S. A. Look, M. T. Burch, W. Fenical, Q. Zheng, J. Clardy, J. Org. Chem. 50 (1985) 5741 6. W. Fenical, R. K. 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An efficient one-pot synthesis of highly substituted furans catalyzed by N-bromosuccinimide

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An efficient one-pot synthesis of highly substituted furans catalyzed by N-bromosuccinimide

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