Antiproliferative activity of new 2-glyco-3-nitro-1,2-dihydroquinolines and quinolines synthesized under solventless conditions promoted by neutral alumina

New Journal of Chemistry c8nj03372b We have presented the Graphical Abstract text and image for your article below. This brief summary of your work will appear in the contents pages of the issue in which your article appears. Q2 Antiproliferative activity of new 2-glyco-3-nitro-1,2dihydroquinolines and quinolines synthesized under solventless conditions promoted by neutral alumina V. Luque-Agudo, Jose ´M. Padro ´n, E. Roma ´n, J. A. Serrano and M. V. Gil* This paper describes the Q3 syntheses of new 2-glyco-3-nitro-1,2dihydroquinolines and 2-glyco-3-nitroquinolines by one-pot aza-Michael–Henry-dehydration reactions using green procedures, such as a minimal amount of solvent combined with an heterogeneous catalyst (neutral alumina). The reactivity of a nitro group-double bond system has also been investigated; thus, addition of indole or pyrrole to N-formylated 1,2-dihydroquinolines has been studied. Finally, the antiproliferative activity of these new compounds has been evaluated against a panel of six human solid tumor cell lines, and compared to pharmacological reference compounds, finding that their activity is in the low micromolar range and that the carbohydrate moiety configuration modulates GI 50 values. Please check this proof carefully. Our staff will not read it in detail after you have returned it. Please send your corrections either as a copy of the proof PDF with electronic notes attached or as a list of corrections. Do not edit the text within the PDF or send a revised manuscript as we will not be able to apply your corrections. Corrections at this stage should be minor and not involve extensive changes. Proof corrections must be returned as a single set of corrections, approved by all co-authors. No further corrections can be made after you have submitted your proof corrections as we will publish your article online as soon as possible after they are received. 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Q5 The sentence beginning ‘‘However, for those...’’ has been altered for clarity. Please check that the meaning is correct. Q6 The sentence beginning ‘‘However, the C-6-bromo- ...’’ has been altered for clarity, please check the meaning has not changed. Q2Antiproliferative activity of new 2-glyco-3-nitro1,2-dihydroquinolines and quinolines synthesized under solventless conditions promoted by neutral alumina† V. Luque-Agudo, a Jose ´M. Padro ´n, b E. Roma ´n, a J. A. Serrano a and M. V. Gil * a This paper describes the syntheses of new 2-glyco-3-nitro-1,2-dihydroquinolines and 2-glyco-3nitroquinolines by one-pot aza-Michael–Henry–dehydration reactions using a minimal amount of solvent and neutral alumina as the heterogeneous catalyst. The reactivity of the nitro group–double bond system has also been investigated; thus, the addition of indole or pyrrole to N-formylated 1,2dihydroquinolines has been studied. Finally, the cytotoxicity and antiproliferative activity of these new compounds have been evaluated against a panel of six human solid tumor cell lines and compared to pharmacological reference compounds, finding that their activity is in the low micromolar range and that the carbohydrate moiety configuration modulates the GI 50 values. Introduction Quinoline 1was first isolated from coal tar in 1834 by F. F. Runge, and it is still the main source of commercial quinoline. 1 Cinchona bark extract (genus Rubiaceae) has been extensively used to combat malaria. Detailed analysis allowed the identification of more than 20 alkaloids, where quinine 2, cinchonidine 3, quinidine 4and cinchonine 5(Fig. 1) were those with the highest biological activity. In general terms, quinoline 1 derivatives exhibit different biological activities, 2–5 and their syntheses have been reviewed. 6 In spite of their numerous applications, there are only a few reported examples of quinoline 1derivatives containing acyclic or cyclic carbohydrate moieties, and none at C-2. 7–11 Regarding the synthesis of nitroquinolines, three general methods have usually been used for their preparation, such as nitration of quinolines, 12 reaction of 3-nitroquinolines N-oxides with a limited number of reagents, 13 and a modified Friedla ¨nder synthesis. 14,15 Dihydroquinolines also present a broad spectrum of biological activities and are very important in medicinal and pharmaceutical chemistry. 16 Synthetic methods of chiral 1,2dihydroquinolines are very limited; 17,18 thus, due to the potential application of these substances, the synthetic challenge of preparing them using carbohydrates, which are considered as attractive products for drug design, as chiral auxiliaries has been considered. Alternative reaction media are being considered in order to comply with the current legislation on environmental, safety and health policies, such as performing the reactions in the absence of solvent, 19 and the combination of this technique with the use of heterogeneous catalysts, which constitutes one of the most powerful green synthetic tools. In this work, the synthesis of 3-nitro-1,2-dihydroquinolines and 3-nitroquinolines bearing carbohydrate moieties at C-2 has been carried out under solventless conditions promoted by neutral alumina, considering, additionally, their possible antiproliferative activity. To the best of our knowledge, there are no reported examples of this type of compound. Due to this lack of available literature, we have based our synthesis on that reported by Yao et al. 15 and adapted it to the asymmetric version using nitroolefins derived from carbohydrates as chiral 1 5 10 15 20 25 30 35 40 45 50 55 1 5 10 15 20 25 30 35 40 45 50 55 Cite this: DOI: 10.1039/c8nj03372b Fig. 1 Structures of compounds 1–5. a IACYS-Unidad de Quı ´mica Verde y Desarrollo Sostenible, Departamento de Quı ´mica Orga ´nica e Inorga ´nica, Facultad de Ciencias, Universidad de Extremadura, 06006 Badajoz, Spain. E-mail: [email protected] b BioLab Instituto Universitario de Bio-Orga ´nica Antonio Gonza ´lez (IUBO-AG), Centro de Investigaciones Biome ´dicas de Canarias (CIBICAN), Universidad de La Laguna, 38206 La Laguna, Tenerife, Spain †Electronic supplementary information (ESI) available. See DOI: 10.1039/ c8nj03372b Received 6th July 2018, Accepted 2nd October 2018 DOI: 10.1039/c8nj03372b rsc.li/njc This journal is cThe Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2018 New J. Chem., 2018, 00,16|1 NJC PAPER inducers. Ballini et al. 20 improved the reaction conditions by avoiding the use of DABCO and benzene. Moreover, since the influence of the structure of the carbohydrate moiety on the cytotoxic and antiviral activity of certain 3-nitrochromenes has been described, 21 the influence of the stereochemistry of the carbohydrate moiety inserted at C-2 of the novel synthesized quinoline-derivatives on their antiproliferative activity has been studied. Results and discussion 2-Glyco-3-nitro-1,2-dihydroquinolines 9a–11c were prepared by onepot aza-Michael–Henry-dehydration reactions between carbohydrate derived nitroalkenes 6and 7and 2-aminobenzaldehydes 8a–c, using neutral alumina as the catalyst, 20 heatingat601C and adding dichloromethane (3.12 mol%) to homogenize the mixture (Scheme 1). The results are summarized in Table 1. Both nitroalkenes were used to compare the asymmetry induced by the chiral center at C-3 of compounds 6and 7and to study whether that skeleton affects the potential antiproliferative activity of the new compounds Q4 (Table 2). The assignment of C-2 configuration for 9a–c and 10a–c + 11a–c was tentatively made, considering that nitroalkenes 6 and 7adopt a preferred conformation 22 in which their C-2 Si and Re faces, respectively, are less hindered for the nucleophilic attack of the amine group present in 8a–c, and, therefore, more favourable (Fig. 2). Processes involving nitroalkene 6were completely diastereoselective, since only one of the two possible diastereoisomers was detected. The observed diastereoselectivity could be explained taking into account the steric hindrance caused by the acetate group at C-3 of compound 6, not found in 7. Our group proposes a correlation between the value of J 1 0 ,2 and the absolute configuration assigned to C-2 in 3-nitro-1,2dihydroquinolines with peracetylated carbohydrate moieties: thus, if C-10presents the Sconfiguration (D-galacto), for compounds with C-2(S) configuration, the coupling constants J 1’,2 will be large (5–10 Hz), whereas for compounds having the C2(R) configuration, these same constants will have a small value (0–2 Hz). When C-10presents the Rconfiguration (D-manno), the values of the coupling constants are opposite with respect to those of the previous case. This correlation has also been observed, and in some cases confirmed by X-ray diffraction, in other 3-nitro-2H-thiochromenes and in 3-nitro-2H-chromenes synthesized in our lab. 23 3-Nitroquinolines 12a–c and 13a–c were obtained by treatment of 1,2-DHQs 9a–c or 10a–c +11a–c with a mixture of sodium dichromate, wet silica gel (50% w/w) and sodium bisulfate 24 at room temperature (Scheme 2), with short reaction times and in good yields (Table 3). Deacetylated quinolines 14a–15c were synthesized (Scheme 3) to improve the solubility of the new compounds in aqueous medium, which is the closest medium to cellular tissue. The results are summarized in Table 4. The trans-nitro group–double bond system is preserved in the skeleton of the 1,2-DHQs; for this reason, we studied their reactivity as acceptors in Michael additions. Thus, reactions between 1,2-DHQs, which were firstly N-formylated 25 to avoid oxidation to the corresponding quinolines, and indole 17 or pyrrole 18 were carried out using basic alumina as the catalyst, 26 heating at 70 1C and adding dichloromethane (3.12 mol%) (Schemes 4 and 5). 1 5 10 15 20 25 30 35 40 45 50 55 1 5 10 15 20 25 30 35 40 45 50 55 Scheme 1 Reaction between nitroalkenes 6and 7and aminobenzaldehydes 8a–c. Table 1 Reaction times, yields and product ratios for 9a and 10a–c +11c products R 2 67 t(days) Yield (%) Product t(days) Yield (%) Product (ratio) H1 89 9a 1.5 88 10a +11a (1 : 1.6) Cl 2 63 9b 1.5 92 10b +11b (1 : 1.6) Br 3 59 9c 287 10c +11c (1 : 1.1) Table 2 Correlation between C-2 configuration and value of J 1’,2 Compound J 1 0 ,2 (Hz) C-2 configuration 9a 9.5 S 9b 9.5 S 9c 9.5 S 10a 0S 11a 6.0 R 10b 1.0 S 11b 5.5 R 10c 1.0 S 11c 5.0 R Fig. 2 Preferential attack of 8a–c on nitroalkene 6. Scheme 2 Oxidation of 9a–c and 10a–c +11a–c to quinolines 12a–c and 13a–c. 2|New J. Chem., 2018, 00,16Thisjournalis cThe Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2018 Paper NJC For processes involving indole 17, the two Z/Erotamers of the same diastereoisomer were isolated, except in the case of 16c, in which only 20c was isolated. However, for those involving pyrrole 18, only Erotamers were isolated in pure form, although Zones were Q5 also detected by 1 H-NMR analysis of the crude reaction. As the NOE experiments were inconclusive, the assignment of Z/Eisomerism was performed by taking into account previous studies. Nagarajan et al. 27 concluded that in the case of N-formyltetrahydroquinolines, the major isomer is E, according to the comparison of chemical shifts of their NMR spectra signals and those of lilolidone, an analogue product. Antiproliferative activity Previous theoretical quantitative structure–activity relationship studies applied to trans-2-(2-nitrovinyl)-furan predicted that more than 50% of the biological activity lies in the trans-nitro group–double bond system. 28 Antiproliferative activity results of structurally-related compounds synthesized by our group 23,29 support this hypothesis. For that reason, the previously mentioned activity of compounds 9a–16c, including the starting nitroolefins 6 and 7, was evaluated against a panel of six human solid tumor cell lines: A-549 (non-small cell lung), SW1573 (non-small cell lung), HBL-100 (breast), T-47D (breast), HeLa (cervix) and WiDr (colon). The GI 50 values (concentration of compound required to inhibit 50% of tumor cell growth) are depicted in Table 5. Evaluation was accomplished by using a slightly modified version of the protocol of the National Cancer Institute (NCI) of the United States. 30,31 The standard anticancer drugs etoposide, cisplatin and 5-fluorouracil were used as references for comparative purposes. As can be observed in Table 5, the GI 50 values of the selected compounds are, in general, worse than those of the reference patterns. Antiproliferative activity oscillates between moderate and low, but, despite that, some conclusions can be inferred: Among the acetylated 3-nitro-1,2-dihydroquinolines with the D-galacto-configuration moiety, 9a–c, the activity decreases in the order R 2 =H4Cl 4Br, for all tumor cell lines. For this set of compounds, 9b was found to be more effective than 5fluorouracil against T-47D and WiDr cell lines, and is also slightly less active than the pharmacological patterns etoposide and cisplatin. The activity of the acetylated 3-nitroquinolines with the D-galacto-configuration moiety, 12a–c, is lower than that of their precursors, the 1,2-dihydroquinolines. However, the C-6bromoQ6substituted compound 12c has moderate activity, exhibiting values comparable to those of 9a for the HeLa cell line. Even so, compound 12b remains the most active in the series against T-47D and WiDr over 5-fluorouracil. It is noteworthy that upon deacetylating the carbohydrate moiety of the 3-nitroquinolines, all compounds turn out to be inactive against all cell lines, except 14c, which exhibits moderate activity, with values very similar to those of 5-fluorouracil against T-47D and WiDr. Pure compound 10a, bearing a D-manno-configuration moiety, has relatively high GI 50 values, being inactive against T-47D and WiDr cell lines. However, it is interesting that the activity of the 10c +11c mixture, which shows a markedly good activity profile, is more effective than 5-fluorouracil and similar to the activity exhibited by cisplatin. 1 5 10 15 20 25 30 35 40 45 50 55 1 5 10 15 20 25 30 35 40 45 50 55 Table 3 Reaction times and yields for the oxidation of 1,2-DHQs 9a–c and 10a–c +11a–c to quinolines 12a–13c Compound R 2 Time (h) Yield (%) 12a H 1.5 83 12b Cl 3.25 87 12c Br 2.25 71 13a H 0.5 47 13b Cl 1.75 76 13c Br 3 85 Scheme 3 Deacetylation of carbohydrate moieties. Table 4 Reaction times and yields for deacetylated compounds 14a–c and 15a–c Compound R 2 Time (h) Yield (%) 14a H1 93 14b Cl 1 95 14c Br 1 66 15a H 1.5 42 15b Cl 1 53 15c Br 1 67 Scheme 4 Addition of indole 17 to compounds 16a–c. Scheme 5 Addition of pyrrole 18 to compounds 16a–c. This journal is cThe Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2018 New J. Chem., 2018, 00,16|3 NJC Paper A significant change of activity was observed upon the Nformylation of the 1,2-dihydroquinolines; thus, all of them present between moderate and good GI 50 values, being of the same order or even lower in the cases of 16b and 16c for tumor cell lines HeLa, T-47D and WiDr, with respect to 5-fluorouracil. For the 3-nitro-1,2-dihydroquinolines and their derivatives, 19a–b,20a–c and 21b–c, it can be concluded that the C-6 substituent of the ring influences the antiproliferative activity of these compounds, but it is not possible to infer a clear trend in this regard. Experimental Materials and methods All chemicals were purchased from commercial sources and used directly, without further purification. Preparative TLC was performed using silica gel (Merck 60 GF 254 ). TLC was performed on precoated Merck Kieselgel 60 GF 254 aluminum backed plates; TLC spots were visualized by UV light. NMR spectra were recorded on a Bruker AC/PC instrument (500 MHz for 1 H and 125 MHz for 13 C) with tetramethylsilane as the internal reference and deuterated chloroform or dimethyl sulfoxide as the solvent. Coupling constants were recorded in Hz. The characterization of NMR signals was based on homonuclear double-resonance and DEPT experiments. High resolution mass spectra were recorded on an Autospec (Micromass) spectrometer, at the Centro de Investigacio ´n Tecnolo ´gica e Innovacio ´n (CITIUS) from the Universidad de Sevilla. Infrared spectra were recorded on an IR3000 Thermo Electron Corporation spectrophotometer in the range between 4000 and 600 cm 1 . The evaluation of the antiproliferative activity was accomplished following the protocol of the NCI of the United States. 30,31 For each compound, the cells were exposed to serial decimal dilutions in the range of 0.001–100 mM for a period of 48 h. After exposure, the SRB method was applied to determine the optical density of each cell at 530 nm (main) and 620 nm (secondary). For each product concentration, the percentage of growth (PG) according to the NCI formulae was calculated. Synthetic procedures General procedure for 2-glyco-3-nitro-1,2-dihydroquinolines 9a–11c. To a heterogeneous mixture of nitroalkenes 6and 732 (1 g, 2.31 mmol) and the appropriate aminobenzaldehyde 8a–c (2.31 mmol), neutral alumina (2.31 g) and four drops of dichloromethane (to initially homogenize the mixture) were added. The mixture was stirred at 60 1C until reaction completion (monitored by TLC, 1 : 5 hexane–diethyl ether). The crude product was extracted with methanol, filtered and washed with the same solvent until the alumina became white. If necessary, diastereoisomers were purified by PTLC (1 : 5 hexane–diethyl ether). General procedure for 2-glyco-3-nitroquinolines 12a–13c. Quinolines were synthesized using a protocol reported in the literature. 24 General procedure for the deacetylated products 14a–15c. To a solution of 12a–13c (1 mmol) in 90% methanol (15 mL), potassium carbonate (0.57 g) was added. The suspension was stirred at room temperature for 1 hour (TLC, 3 : 1, benzene– methanol). The crude reaction was acidified to pH B6 with diluted HCl (if a solid appears) or Amberlite IR-120 (H + ), which was then filtered. Pure products were crystallized from methanol. General procedure for N-formyl-1,2-dihydroquinolines 16a– c. A mixture of 9a–c (1 mmol), formic acid (4.7 mmol) and acetic anhydride (4.8 mmol) was stirred at room temperature for 1–2 hours (TLC, 1 : 5 hexane–diethyl ether). After evaporation, the 1 5 10 15 20 25 30 35 40 45 50 55 1 5 10 15 20 25 30 35 40 45 50 55 Table 5 Antiproliferative activity (GI 50 ) against human solid tumor cell lines and human fibroblasts a Compound A549 (lung) HBL-100 (breast) HeLa (cervix) SW1573 (lung) T-47D (breast) WiDr (colon) BJ-hTert (fibroblast) GI 50 s D (mM) 617 4142162 1.7 0.7 19 21834211 720 2103181 2.1 0.4 22 4245113 9a 29 47329 33 86726 71 25 53 16 4100 12a 70 28 72 26 38 77239 4100 90 18 n.t. 14a 4100 4100 4100 4100 4100 4100 n.t. 10a 57 43483012684100 4100 n.t. 15a 4100 4100 4100 4100 4100 4100 n.t. 16a 56 17 83 23 43 46310 54 15 56 16 4100 9b 25 92662494092363034100 12b 37 54100 26 69013214713 n.t. 14b 4100 4100 4100 4100 4100 4100 n.t. 15b 4100 4100 4100 4100 4100 4100 n.t. 16b 15 21711631231841944100 9c 88 17 97 55239112 93 12 82 24 4100 12c 53 16 89 24494113 82 17 59 94100 14c 29 53233275415010 49 14100 10c +11c 3.3 0.4 8.2 2.6 3.4 0.6 2.6 0.6 2.6 0.2 4.3 0.4 4100 15c 4100 4100 4100 4100 4100 4100 n.t. 16c 19 43181841532872644100 Etoposide 0.7 0.2 2.3 0.9 3.0 0.9 15 2226233 1.3 0.6 5-Fluorouracil 2.2 0.3 5.5 2.3 15 5 4.3 1.6 47 18 49 7 5.5 0.5 Cisplatin 2.1 0.6 1.9 0.2 2.0 0.3 3.0 0.4 15 3266143 a Values are mean of two to four experiments. n.t. = not tested. 4|New J. Chem., 2018, 00,16Thisjournalis cThe Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2018 Paper NJC residue was dissolved in dichloromethane (10 mL), washed with 5% sodium bicarbonate solution and dried with magnesium sulfate. The extract was evaporated to yield pure compounds 16a–c. General procedure for the addition of indole or pyrrole to Nformyl-1,2-dihydroquinolines. To a mixture of N-formyl-1,2dihydroquinolines 16a–c (1 mmol) and indole or pyrrole (1 mmol), activated basic alumina (1 g) and four drops of dichloromethane (to initially homogenize the mixture) were added and stirred at 60–70 1C for two days. The crude reaction was extracted with methanol and filtered. Compounds were purified by PTLC (1 : 1 hexane–ethyl acetate, 2 elutions). Conclusions In this paper, we report on the synthesis of new 3-nitro-1,2dihydroquinolines and derivatives bearing a carbohydrate moiety at C-2 using green procedures, since these processes have been carried out in the absence of solvent and with a heterogeneous catalyst. Moreover, the antiproliferative activity of some of the products described herein has been studied, finding that their GI 50 values are of the same order as those of pharmacological reference compounds in some of the cases. Conflicts of interest There are no conflicts to declare. Acknowledgements This work was supported by the Gobierno deGobierno de Extremadura-Ayuda a Grupos de Investigacio ´n Catalogados and Fondo Europeo de Desarrollo Regional (Grant GR15022). We also thank the Universidad de Extremadura, Plan de Iniciacio ´n a la Investigacio ´n, Desarrollo Tecnolo ´gico e Innovacio ´n 2016 and Grupo Banco Santander for providing a fellowship to Vero ´nica Luque-Agudo. Notes and references 1 R. Heusch and B. Laverkusen, Ullmann’s Encyclopedia of Industrial Chemistry, 2000, , DOI: 10.14356007: a09_297. 2(a) O. Bilker, V. Lindo, M. Panico, A. E. Etiene, T. Paxton, A. Dell, M. Rogers, R. E. Sinden and H. R. Morris, Nature, 1998, 392, 289; (b) G. Roma, M. D. Braccio, G. Grossi, F. Mattioli and H. Ghia, Eur. J. Med. Chem., 2000, 35, 1021; (c) Y.-L. Chen, K.-C. Fang, J.-Y. Sheu, S.-L. Hsu and C.-C. Tzeng, J. Med. Chem., 2000, 44, 2374; (d) P. A. Winstanley, Parasitol. Today, 2000, 16, 146. 3(a) K.-C. Fang, Y.-L. Chen, J.-Y. Sheu, T.-C. Wang and C.- C. Tzeng, J. Med. Chem., 2000, 43, 3809; (b) J. Chevalier, S. Atifi, A. Eyraud, A. Mahamoud, J. Barbe and J.-M. Pages, J. Med. Chem., 2001, 44, 4023; (c) L. T. Phan, T. Jian, Z. Chen, Y.-L. Qiu, Z. Wang, T. Beach, A. Polemeropoulos and Y. S. Or, J. Med. Chem., 2004, 47, 2965; (d) S. J. Benkovic, S. J. Baker, M. R. K. Alley, Y.-H. Woo, Y.-K. Zhang, T. Akama, W. Mao, J. Baboval, P. T. R. Rajagopalan, M. Wall, L. S. Kahng, A. Tavassoli and L. Shapiro, J. Med. Chem., 2005, 48, 7468. 4(a) K. Majerz-Maniecka, B. Oleksyn, R. Musiol, B. Podeszwa and J. Polanski, Abstracts of Papers, Joint Meeting on Medicinal Chemistry, Vienna, Austria, June 20–23, 2005; In Sci. Pharm., 2005, 73 (Suppl. 1), 194; (b) L. Y. Vargas, M. V. Castelli, V. V. Kouznetsov, J. M. Urbina, S. N. Lopez, M. Sortino, R. D. Enriz, J. C. Ribas and S. Zacchino, Bioorg. Med. Chem., 2003, 11, 1531; (c) M. Shingh, M. P. Shingh and S. Y. Ablordeppey, Drug Dev. Ind. Pharm., 1996, 22, 377. 5(a) L. Dassonneville, A. Lansiaux, A. Wattelet, N. Wattez, C. Mahieu, S. V. Miert, L. Pieters and C. Bailly, Eur. J. Pharmacol., 2000, 409,9;(b) L. Dassonneville, K. Bonjean, M.-C. De Pauw-Gillet, P. Colson, C. Houssier, J. Quentin-Leclerq, L. Angenot and S. Y. Ablordeppey, Bioorg. Med. Chem., 2002, 10, 1337; (c) C. Bailly, Biochemistry, 1999, 38, 7719; (d) C. Bailly, W. Laine, B. Baldeyrou, M.- C. De Pauw-Gillet, P. Colson, C. Houssier, K. Cimanga, S. V. Miert, A. J. Vlietinck and L. Pieters, Anti-Cancer Drug Des., 2000, 15, 191; (e) M. Chauhan, A. Rana, J. M. Alex, A. Negi, S. Singh and R. Kumar, Bioorg. Chem., 2015, 58,1. 6 S. M. Prajapati, K. D. Patel, R. H. Vekariya, S. N. Panchal and H. D. Patel, RSC Adv., 2014, 4, 24463, and references therein. 7 P. H. Dobbelaar and C. H. Marzabadi, Tetrahedron Lett., 2010, 51, 201. 8(a)J.S.Yadav,B.V.S.ReddyandB.Padmavani,Synthesis, 2004, 405; (b)J.S.Yadav,B.V.S.Reddy,S.Meraj,P.Vishnumurthy, K. Narsimulu and A. C. Kunwar, Synthesis, 2006, 2923. 9(a) C. T. Bahner, N. Hunt and L. M. Rives, J. Org. Chem., 1960, 25, 2062; (b) S. Ou, Z. Lin, C. Duan, H. Zhang and Z. Bai, Chem. Commun., 2006, 4392. 10 J. Godlewska, K. Badowsca-Roslonek, J. Ramza, L. Kaczmarek, W. Peczynska-Czoch and A. Opolski, Radiol. Oncol., 2004, 38, 137. 11 S. Nagarajan and T. M. Das, Carbohydr. Res.,2009,344,1028. 12 (a) G. Bacharach, A. H. Haut and L. Caroline, Recl. Trav. Chim. Pays-Bas, 1933, 413; (b) B. Arnestad, J. M. Bakke, I. Hegbom and E. Ranes, Acta Chem. Scand., 1996, 50, 556; (c) J. M. Bakke and E. Ranes, Synthesis, 1997, 281; (d) M. Bakke, E. Ranes, J. Riha and H. Svensen, Acta Chem. Scand., 1999, 53, 141. 13 (a) H. Nakagawa, T. Higuchi, K. K. Kikuchi, Y. Urano and T. Nagano, Chem. Pharm. Bull., 1998, 46, 1656; (b) K. S. Sharma, S. Kumari and R. P. Singh, Synthesis, 1981, 316. 14 (a) K. Schofield and R. S. Theobald, J. Chem. Soc., 1950, 395; (b) K. Schofield and R. S. Theobald, J. Chem. Soc., 1951, 2992; (c) D. W. Ockenden and K. Schofield, J. Chem. Soc., 1953, 3914; (d) H. E. Baumgarten and J. L. Taylor, J. Am. Chem. Soc., 1957, 79, 1502. 15 M. C. Yan, Z. Tu, C. Lin, S. Ko, J. Hsu and C.-F. Yao, J. Org. Chem., 2004, 69, 1565. 16 (a) A. R. Katritzky, S. Rachwal and B. Rachwal, Tetrahedron, 1996, 52, 15031; (b) K. M. Witherup, R. W. Ransom, 1 5 10 15 20 25 30 35 40 45 50 55 1 5 10 15 20 25 30 35 40 45 50 55 This journal is cThe Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2018 New J. Chem., 2018, 00,16|5 NJC Paper A. C. Graham, A. M. Pitzenberger and S. L. Varg, J. Am. Chem. Soc., 1995, 117, 6682; (c) R. M. Kariba, P. J. Houghton and A. J. Yenesew, J. Nat. Prod., 2002, 65, 566; (d) S. W. Elmore, M. J. Coghlan, D. D. Anderson, J. K. Pratt, B. E. Green, A. X. Wang, M. A. Stashko, C. W. Lin, C. M. Tyree, J. N. Miner, P. B. Jacobson, D. M. Wilcox and B. C. Line, J. Med. Chem., 2001, 44, 4481; (e) P. D. Leeson, R. W. Carling, K. W. Moore, A. M. Moseley, J. D. Smith, G. Stevenson, T. Chan, R. Baker and A. C. Foster, J. Med. Chem., 1992, 35, 1954. 17 (a) M. Takamura, K. Funabashi, M. Kanai and M. Shibasaki, J. Am. Chem. Soc., 2000, 122, 6327; (b) H. Li, J. Wang, H. Xie, L. Zu, W. Jiang, E. N. Duesler and W. Wang, Org. Lett., 2007, 9, 965; (c) H. Sunden, R. Rios, I. Ibrahem, G.-L. Zhao, L. Eriksson and A. Co ´rdova, Adv. Synth. Catal., 2007, 349, 827; (d) X. Liu and Y. Lu, Org. Biomol. Chem., 2010, 8, 4063. 18 Y.-F. Wang, W. Wang, W. Zhang, S.-P. Luo, B.-L. Li, A.-B. Xia, A.-G. Zhong and D.-Q. Xu, Chem. – Asian J., 2009, 4, 1834. 19 Chemistry in Alternative Reaction Media, ed. D. J. Adams, P. J. Dyson and S. J. Tavener, Wiley, 2004. 20 R. Ballini, G. Bosica, D. Fiorini and A. Palmieri, Green Chem., 2005, 7, 825. 21 J. M. J. Tronchet, S. Zerelli, N. Dolatshahi and H. Tu ¨rler, Chem. Pharm. Bull., 1988, 36, 3725. 22 (a) J. C. Sowden and M. L. Oftedahl, J. Org. Chem., 1961, 26, 2153; (b) J. C. Sowden and M. L. Oftedahl, J. Am. Chem. Soc., 1960, 82, 2303; (c) J. C. Sowden, A. Kirkland and K. O. Lloyd, J. Org. Chem., 1963, 28, 3516; (d) J. A. Galbis and J. A. Serrano, An. Quim., 1983, 79, 33. 23 V. Luque-Agudo, J. Albarra ´n-Velo, J. G. Ferna ´ndez-Bolan ˜os, O. Lo ´pez, M. E. Light, J. M. Padro ´n, I. Lagunes, E. Roma ´n, J. A. Serrano and M. V. Gil, New J. Chem., 2017, 41, 3154. 24 J. A. Damavandi, M. A. Zolfigol and B. Karami, Synth. Commun., 2001, 31(20), 3183. 25 M. L. Hill and R. A. Raphael, Tetrahedron, 1990, 46, 4587. 26 R. Ballini, R. R. Clemente, A. Palmieri and M. Petrini, Adv. Synth. Catal., 2006, 348, 191. 27 K. Nagarajan, M. D. Nair and P. M. Pillai, Tetrahedron, 1967, 23, 1683. 28 H. Gonza ´lez-Dı ´az, E. Olaza ´bal, L. Santana, E. Uriarte, Y. Gonza ´lez-Dı ´az and N. Castan ˜edo, Bioorg. Med. Chem., 2007, 15, 962. 29 V. Luque-Agudo, A. M. Gonza ´lez-Gutie ´rrez, I. Lagunes, F. Lo ´pez-Galindo, J. M. Padro ´n, E. Roma ´n, J. A. Serrano and M. V. Gil, Bioorg. Chem., 2016, 69, 71. 30 P. Skehan, R. Storeng, D. Scudiero, A. Monks, J. McMahon, D. Vistica, J. T. Warren, H. Bokesch, S. Kenney and M. R. Boyd, J. Natl. Cancer Inst., 1990, 82, 1107. 31 P. Miranda, J. M. Padro ´n, J. I. Padro ´n, J. Villar and V. S. Martin, ChemMedChem, 2006, 1, 323. 32 (a) J. C. Sowden and D. R. Strobach, J. Am. Chem. Soc., 1960, 82, 954; (b) J. C. Sowden and R. Schaffer, J. Am. Chem. Soc., 1950, 73, 4662. 1 5 10 15 20 25 30 35 40 45 50 55 1 5 10 15 20 25 30 35 40 45 50 55 6|New J. Chem., 2018, 00,16Thisjournalis cThe Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2018 Paper NJC