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Tetrahedron 71 (2015) 1269e1275

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Tetrahedron
journal homepage: www.elsevier.com/locate/tet

Palladium-catalyzed decarboxylative C3-acylation of benzofurans
and benzothiophenes with a-oxocarboxylic acids via direct sp2 CeH
bond activation
Wei-Jie Gong a, De-Xian Liu a, *, Fei-Long Li a, Jun Gao a, Hong-Xi Li a, *, Jian-Ping Lang a, b, *
a
College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou 215123, PR China
b
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 210032, PR China

a r t i c l e i n f o a b s t r a c t

Article history: An efficient approach to decarboxylative C3-acylation of benzothiophenes or benzofurans with a-ox-
Received 9 November 2014 ocarboxylic acids via palladium-catalyzed CeH bond activation was developed. This method was com-
Received in revised form 22 December 2014 patible with a variety of functional groups and provided an attractive route to 3-acylbenzothiophenes
Accepted 29 December 2014
and 3-acylbenzofurans in good to high yields.
Available online 9 January 2015
Ó 2015 Elsevier Ltd. All rights reserved.

Keywords:
Decarboxylation
Palladium(II)
Benzofuran
Benzothiophene
Acylation
a-Oxocarboxylic acids

1. Introduction with n-BuLi, dimethylformamide, and chloroacetone provided
2-acetylbenzothiophene.6f These methods required, a multistep
The (hetero)aryl ketones are fundamental building blocks for synthesis of starting material, or the use of toxic carbon monoxide,
natural products, medicinally-relevant molecules, and organic unstable diazo compounds, and pyrophoric n-BuLi, and led to the
functional materials.1 More specifically, acylbenzothiophene and formation of a mixture of regioisomers. Traditionally, the simple
acylbenzofuran have attracted considerable attention in the phar- and straightforward method for the synthesis of acylbenzothio-
maceutical chemistry.2 For example, the 3-acylbenzofuran de- phenes or benzofurans appeared to be the FriedeleCrafts acylation
rivatives, benzbromarone, and amiodarone (Scheme 1), are reactions,7 which, however, involved the use of excess AlCl3, had
employed as the uricosuricagent3 and antiarrhythmic agents,4 re- poor regioselectivity, and led to the formation of environmentally
spectively. The aryl-benzothiophenyl ketone, raloxifene (Scheme 1), harmful gaseous HCl. Therefore, screening out simple and practical
can be used as the vasodilator.5 There are numerous synthetic
approaches6 to C2 or C3-acyl benzofuran and benzothiophene
derivatives, including palladium-catalyzed cross-coupling reaction
of arylboronic acids, carbon monoxide, and aryl iodides,6a photo-
reactions of arenecarbothioamides with benzofuran or benzothio-
phene in benzene,6b reduction, S-alkylation, re-oxidation, and
cyclization of 2-mercaptobenzoic acids,6c reaction of benzothio-
phene with carboxylic acids and trifluoroacetic anhydride in the
presence of H3PO4,6d reaction of o-thioalkyl and o-thioaryl
substituted phenyl radicals with alkynes.6e Reaction of thiophenol

* Corresponding authors. Tel.: þ86 512 6588 2865; fax: þ86 512 6588 0328; Scheme 1. Some structures of bioactive 3-acylbenzofuran and 3-acylbenzothiophene
e-mail address: jplang@suda.edu.cn (J.-P. Lang). derivatives.

http://dx.doi.org/10.1016/j.tet.2014.12.095
0040-4020/Ó 2015 Elsevier Ltd. All rights reserved.

reagents. solvent dependence of the acylation was observed. 21 h. The screening of catalysts O-methyl oximes.5:1.2 mmol). and decarboxylative acylation of heteroarenes by CeH functionalization is Pd2(dba)3 (dba¼dibenzylideneacetone) (entries 2e5). acylbenzofurans and 3-acylbenzofurans.1270 W. b GC yields. solvent (1. phenylacetamides. As shown in Table 1 (entries 14e18).5:1.5:1 87 7 Pd(PPh3)4 AgOAc K2S2O8 7. (benzyl)(aryl)sulfane. Solvent screening revealed that the optimal results could ylating agents and chlorobenzene as a solvent.0 equiv).4-dioxane/AcOH/DMSO in prompted chemists to develop new convenient methodology to get 3.5:1 16 12 Pd(PPh3)4 K2S2O8 TBAB 7. or 2-phenylpyridines or benzoic acids with a-oxocarboxylic in 84% yield (entry 1). coupling reaction of 2-(benzothiophen-2-yl)pyridine (1) and ylic acids as acylating resources8 has been an attractive synthetic 2-oxophenylacetic acid (2a) in the presence of 10 mol % Pd(PPh3)4 method for the formation of aryl ketones.5:1.5:1 7 13 Pd(PPh3)4 Ag2O TBAB 7.5:1.5:1.5:1 40 8 Pd(PPh3)4 Cu(OAc)2 K2S2O8 7. As an extension of our pro. Very (entry 5) when tetrabutyl ammonium bromide (TBAB) was added recently. as follow: 10 mol % Pd(PPh3)4.5:1 28 14 Pd(PPh3)4 Ag2O K2S2O8 TBAB 1.4-dioxane/HOAc/DMSO at 120  C gave rise to CO2 instead of toxic metal compounds.5:1.14 we herein Therefore. idin-2-yl)benzothiophen-3-yl)methanone (3a) could be obtained anilides. In the past decade. Although the decarboxylative arylation of benzofuran or and Cu(OAc)2 (entries 7 and 8).10 As far as the than Pd(TFA)2 (TFA¼trifluoroacetate).0 equiv of Ag2O. The control experiments carbonylative direct acylation of five-membered and condensed showed that Pd(PPh3)4. 2. at 120  C under air.4-Dioxane/HOAc/DMSO Yieldb (%) 1 Pd(PPh3)4 Ag2CO3 K2S2O8 7. 120  C. with Ag2CO3 (2 equiv) as a decarboxylative reagent. we began to acids. palladium reagent (0. After 21 h.5:1.5 mL). a strong ate to good yields. co-oxidant (0.01 mmol). PdCl2.5:1 28 9 Pd(PPh3)4 Ag2O (NH4)2S2O8 7.5:1 26 10 Pd(PPh3)4 Ag2O K2S2O8 TBAB 7. Beller and co-workers13a reported ruthenium-catalyzed into the catalytic system (entry 10).0 equiv of furan and benzothiophene with the a-oxocarboxylic acid via palla.5:1 79 3 PdCl2 Ag2CO3 K2S2O8 7. the decarboxylative acylation of unactivated Our investigation started with the decarboxylative cross- arenes through metal-catalyzed CeH activation using a-oxocarbox.2 mmol). K2S2O8.12 the Pd-catalyzed decar. azobenzenes.5:1. K2S2O8 quire the use of stoichiometric organometallic coupling reagents and (2 equiv) as the co-oxidant in 1.5:1. ject on the oxidative decarboxylative coupling reactions. Pd(OAc)2. Ag2O (entry 6) seemed better than Ag2CO3 (entry 1). The yield of 3a decreased with reduced amount of Ag2O or K2S2O8. Ge and co-workers under air (Table 1).5:1 1.5:1.5:1.9 After that the metal-mediated decarboxylative ortho-acylation optimize the reaction conditions with respect to different palla- of O-methyl ketoximes.5:1 96 11 Ag2O K2S2O8 TBAB 7. Ag2O. resulting product was dramatically increased from 87% to 96% boxylative acylation of C(sp2)eH bond has never been reported.1 mmol). Results and discussion phene remains a great challenge. and K2S2O8 were required for this heterocycles with toxic carbon monoxide and aryliodides in moder. 2a (0.0 equiv).5:1. It was noted that the yield of benzothiophene has been well explored.4-dioxane/HOAc/DMSO dium-catalyzed C(sp2)eH activation. oxidant (0. Gong et al. providing the product (3a) in 96% yield. 2. . dium catalysts. 1.13b have demonstrated Pd-cat. azole and their derivatives11 have been ex.5:1 58 20d Pd(PPh3)4 Ag2O K2S2O8 TBAB 7. These limitations be obtained with a co-solvent of 1. Han and Pan et al.0 equiv of TBAB in 7.2 mmol).5:1 84 2 Pd(TFA)2 Ag2CO3 K2S2O8 7. 2.5:1 78 6 Pd(PPh3)4 Ag2O K2S2O8 7. AgOAc plored. oxidants. d K2S2O8 (1.5:1 73 5 Pd2(dba)3 Ag2CO3 K2S2O8 7. O-phenyl carbamates. Such methods did not re. For the oxi- concerned. c Ag2O (1.5:1 69 a Reaction conditions: 1 (0. Oxidant Co-oxidant Additive 1. Table 1 Optimization of the reaction conditions for the decarboxylative C3-acylation of 2-(benzothiophen-2-yl)pyridine with a-oxocarboxylic acida Entry Cat. and solvents.5:1. dants.5:1. The yield of the alyzed C3-acylation of benzofurans and benzothiophenes by desired product was very low in the absence of one of these three dehydrogenative coupling reaction using unstable aldehydes as ac.5:1 76 4 Pd(OAc)2 Ag2CO3 K2S2O8 7. indicated that for catalyzing the decarboxylative cross-coupling cyclic enamides.4-Dioxane 22 15 Pd(PPh3)4 Ag2O K2S2O8 TBAB DMSO 14 16 Pd(PPh3)4 Ag2O K2S2O8 TBAB HOAc 15 17 Pd(PPh3)4 Ag2O K2S2O8 TBAB 7:2:1 73 18 Pd(PPh3)4 Ag2O K2S2O8 TBAB 4:1:d 62 19c Pd(PPh3)4 Ag2O K2S2O8 TBAB 7. a volume ratio of 7. azoxybenzenes. Encouraged by this initial result. / Tetrahedron 71 (2015) 1269e1275 processes for the syntheses of acylbenzofuran and acylbenzothio. Pd(PPh3)4 (entry 1) was more effective with a-oxocarboxylic acids have been reported. and 1.5:1.5:1. 2-aryloxypyridines.5:1.5:1. the optimal reaction conditions were finally established report an alternative protocol to achieve the C3-acylation of benzo. coupling reaction.0 equiv of tetrabutyl ammonium bromide (TBAB). only indole. and 2-phosphorylbiphenyl reactions of 1 with 2a.-J. the desired product phenyl(2-(pyr- disclosed Pd-catalyzed decarboxylative C(sp2)eH acylation of acet.

underwent the reaction smoothly to give the product 3k in 84% Secondly. oxidized into the active Pd(II) catalyst with K2S2O8.5:1) at 120  C in air. The electron-rich and -neutral derivatives. acid did not hamper the decarboxylative acylation reaction Interestingly. using Ag2CO3 as a decarboxylative benzothiophene units. The remarkable features of this methodology include good gave higher yields (90%) than that in 1. (5j.10.4- dioxane/HOAc/DMSO produced phenyl(2-(pyridin-2-yl)benzofu. we have demonstrated an efficient approach to the ran-3-yl)methanone in 71% yield. In summary.4-dioxane/HOAc/DMSO. the reaction carried out in 1. to gen- 2-thienylglyoxylic acid and 2-furylglyoxylic acid also provided erate the acylePd(II) intermediate III. high yields could be obtained with p-fiuoro (3e).and 2-furyl-benzofuryl ketones were obtained in 74% and were tolerated under the reaction conditions. 71%) or bromo groups (5g. the intermediate III bisheteroaryl ketone products (3l and 3m) in moderate yields undergoes the reductive elimination to produce the desired ketone (64% and 67%). product and Pd(0). K2S2O8 as a co-oxidant in 1. It 2-arylglyoxylic acids containing different functional groups in the provides a highly versatile alternative to the existing methods for aromatic ring also showed good reactivity to give the products in building the biologically important C3-acylated benzofuran and good to high yields (5ae5m). The According to the previous reports.-J. In the case with a-oxocarboxylic acids via palladium-catalyzed CeH activa- of the solvent. which yield. p-bromo (3g). in Table 2. 2-thienylglyoxylic acid and 2-furylglyoxylic acid. above. although it was not surprising that halogens 2-thienyl.11 we propose the possible electron-rich and electron-deficient 2-arylglyoxylic acids afforded catalytic reaction mechanism (Scheme 2) to account for the the corresponding 3-acylbenzothiophene products 3be3j in aforementioned results. we also investigated the decarboxylative acylation reactions of 2-(benzofuran-2-yl)pyridine (4) with various phenylglyoxylic acids under the optimal reaction conditions. It seemed that tional groups in the aromatic ring showed high reactivity to give the o-substituted chloro group on phenyl rings of 2-oxophenylacetic the corresponding products in good to high yields (3ae3m). W. 5h. However. 73%.4-dioxane/HOAc/DMF (v/v/ pharmacologically important benzofuran and benzothiophene v¼7. chloro (5f. When Ag2CO3 was replaced by decarboxylative C3-acylation of benzofurans and benzothiophenes Ag2O. Firstly. the moderate yields were observed for 2-arylglyoxylic compatibility of substituted phenylglyoxylic acids was summarized acids with electron-withdrawing groups such as fluoro (5e. 71%). the regenerated Pd(0) catalyst can be re- Encouraged by the high efficiency for the reactions of 2-(ben. Meanwhile. It is noteworthy that the heterocyclic a-keto acids such as is formed from the silver-mediated decarboxylation of 2. The reaction of 4 and 2a 3. Conclusions catalyzed by Pd(PPh3)4 in the presence of Ag2CO3 and K2S2O8 in 1. 79% isolated yields. Various 2-arylglyoxylic acids containing different func. the ortho-palladation of 1 or 4 with 76e95% yield. the corresponding nylglyoxylic acids. However. Finally. thereby fur- zothiophen-2-yl)pyridine with a-oxocarboxylic acids described nishing the catalytic cycle. and m-bromo (3h) substituted phe. the re. respectively (Table 3). we turned our 2-arylglyoxylic acids proceeded smoothly to form the correspond- attention to investigate the scope of the decarboxylative acylation ing 3-acylbenzofurans in more than 90% isolated yields (5ae5d and of 2-(benzothiophen-2-yl)pyridine with a-oxocarboxylic acids. the similar reaction gave the product in 78% yield. The 5i). Table 2 Palladium-catalyzed C3-acylation of 2-(benzo[b]thiophen-2-yl)pyridine with a-oxocarboxylic acidsa . action did not show any obvious electronic preference.4-dioxane/HOAc/DMF tion.5:1. 2-(naphthalen-2-yl)-2-oxoacetic acid Pd(II) to provide the five-membered palladacycle intermediate I. Gong et al. the intermediate I reacts with the intermediate II. The product yields and wide tolerance of various functional groups. For the heteroaromatic a-oxocarboxylic acids such as p-chloro (3f). 77%). Thirdly. / Tetrahedron 71 (2015) 1269e1275 1271 With the optimized reaction conditions in hand. 90%). It is also applicable to the synthesis of more reagent.

2 mmol).3. 122. 7.2 ppm. The reaction mixture was stirred vigorously at 120  C parts per million (ppm) relative to. 144. After the filtrate was con- centrated under reduced pressure.87 (d. 2H). Resonance patterns were reported with the notations of s (singlet). 124.6.9.0 Hz.92 (d.2.88e7.20 (m.2. 136. 2H). 4. CDCl3): d¼152. 148.73 (m. DMSO- d6): d¼8.1.1.80 (m.1.0 Hz. 140.7.2. In addition. Pyridine was distilled from CaH2. Ag2O (0.33 (m.4. 121. All reactions were performed under air atmosphere unless stated otherwise.8 ppm.9. 2-(Benzofuran-2-yl)pyridine (4).88e7. 7. General coupling constants J were reported in hertz (Hz).65e8. 150.86 (m. Commercially available reagents were used as 4.2. 155. 1H).76e7. 2H). 2-(Benzo[b]thiophen-2-yl)pyridine (1). the TMS as the in an oil bath for 21 h.4.82e7.76e7. CDCl3): d¼8. 1H) ppm.63 (m. The uncorrected melting points were re-determined on a Mel-Temp II apparatus.73 (m.38e7. 149.2 mmol).4-dioxane/HOAc/DMSO (1.1272 W. 4. 1H NMR and 13C NMR spectra were recorded at ambient ammonium bromide (TBAB) (0. 125. 105. 123. 7. 2H).48e8. J¼4.23e7. Gong et al. 120.6. 1H).1 mmol). K2S2O8 (0. 1H).2.0. 1H NMR (400 MHz. General procedure for the acylation of benzothiophene received without purification. d¼8. 7.-J. 119. and temperature on a Varian NITYplus-400. umn chromatography was carried out on silica gel (300e400 a-oxocarboxylic acids (0. 122.5. 111. v/v/ used as deuterated solvents. 7.63 (m. The proposed reaction mechanism. respectively.13b a-Oxocarboxylic A sealed reaction tube equipped with a magnetic stirring bar acids were synthesized according to the reported method. 137. Yellow solid. 7. 124. 7.1 mmol).20 (m. 123.3. CDCl3): Scheme 2.3. Phenyl(2-(pyridine-2-yl)benzo[b]thiophen-3-yl)methanone (3a). 1H). .7. 2H). 7. 7.9. 7. 2H). / Tetrahedron 71 (2015) 1269e1275 Table 3 Palladium-catalyzed C3-acylation of 2-(benzofuran-2-yl)pyridine with a-oxocarboxylic acidsa 4. 125. 1H).9. 128. Then it was cooled to room temperature and diluted with ethyl acetate and filtered.01 mmol) in 1.82e7. CDCl3 and DMSO-d6 were Pd(PPh3)4 (0.6.15 Col.38e7.7.2. The chemical shifts d were reported as v¼7. 13C NMR (400 MHz. Mp 74e75  C.5:1. d (doublet).9. was charged with 2-(benzothiophen-2-yl)pyridine (0. 1H). the residue was purified through the flash column chromatography on silica gel to afford the desired products.33 (m.2 mmol). 7. 2H). and m (multiplet). 1H NMR (400 MHz. 7.23e7.7.3.47 (m. J¼4. 122. 1H). 1H NMR (400 MHz.5 mL.6. 140. 4.80 (m. 13C NMR (400 MHz. 4. tetrabutyl mesh). DMSO-d6): d¼155.8.8. Experimental internal standard.5:1). or benzofuran with a-oxocarboxylic acid 2-(Benzo[b]thiophen-2-yl)pyridine and 2-(benzofuran-2-yl)pyri- dine were prepared according to the literature.65e8.86 (m.

55 (m. 1H).3.8.5. 143.2. 122.46 (m. 125.92 (d.10 -Biphenyl](2-(pyridin-2-yl)benzo[b]thiophen-3-yl)meth- anone (3d).0. Yellow solid.2. 115.1.3. 2H).5. 133.08 (m.2. 159. J¼8. 147. 132.91 (d. 8. LC-MS 143. 7.9. Mp 99e100  C.9.4. 133.4 ppm. 7. 7. 1H). J¼8. found: 346. 126. LCeMS (EI): m/z calcd m/z calcd [Mþ1]þ¼322. 139. 123.15 (m. 122. 122.4.39 (m.3. 7. 3. 1H) ppm.51e7. White solid.1. 135.7 ppm.29e7.1.5. W. (2-(Pyridin-2-yl)benzo[b]thiophen-3-yl)(p-tolyl)methanone 4. 7. J¼4.6. 122.50e7.1. 7.44e7.12.8. J¼8.8. d¼193.93 (m. 7. 143. 3H).2. d¼8. 135.8. found: 394. Mp 102e103  C. 2H). 1H).8. 1H).77 (t.9. 125. LCeMS (EI): m/z calcd [Mþ1]þ¼306. 131. 149.52 (d. 13C NMR (400 MHz.11 (m. 1H NMR (400 MHz.91 (d.44e8. 134. d¼8.35 (m. 7.4 ppm. 123.0. 128.0.0 Hz.14. 1H). 2H).5. LCeMS (EI): m/z calcd [Mþ1]þ¼346.5. Phenyl(2-(pyridin-2-yl)benzofuran-3-yl)methanone 4.39 (t.73e7. 2H).2. 122.7.2.0.0.81 (d.1. 151. 1H).13.68e7.04e7. 147.3.4.30e7.52 (m.0 Hz. 149. J¼8.50e8. J¼4. 133. 131. 1H). 2H).70e7.8. 7.8. 13C NMR (400 MHz.6. 7. 7.8. (4-Bromophenyl)(2-(pyridin-2-yl)benzo[b]thiophen-3-yl) (5a). 7. 4.51 (m. 13C NMR (400 MHz. 1H).52e7.91 (d.4. 8. 5H). 1H).3. 133.7.14 (m.12e7. 122.4. 7. 3H).6.0.3.34 (m.4.6. 7. 139. 125. 134. CDCl3): d¼191.6.0.46 (d.92e6. 151.8. 121. LCeMS (EI): 112.15. 136. 139. 1H) ppm. CDCl3): methanone (3g).84 (d.7. 154. 1H). 139. 125. 1H). 122. 6H). found: 394. 132. 1H).1.49 (d. 1H NMR (400 MHz.42e7. 1H NMR (400 MHz. 128. 7.7 ppm. 132.91 (m. 1H).0. 122. 136.60e8. 1H NMR (400 MHz. 7.0 Hz.0 Hz. 13C NMR (400 MHz. 2H). 7. 139.0 Hz. 4.34 (s.26 (m. 2H).0 Hz.1. 139.56e7. 7.8.1. 7.7. Mp 100e102  C.6. 126.5.41 (m. 132.0.0. J¼8.86 (d. 1H). 2H).6. 129.1. 149. 131.6.43 (m. Yellow solid.8. 122. 125.9. 150. (Naphthalen-2-yl)(2-(pyridin-2-yl)benzo[b]thiophen-3-yl) CDCl3): d¼8.0 Hz.3 ppm. 1H NMR (400 MHz. 2H). 125.1.16 (m.0. 124.11 (m. 136. 118.0.5. 1H). 136. 1H NMR (400 MHz.9. 123. J¼8.17e7.09e7.1. 7.19 (m. 150.3.51e7. 1H NMR (400 MHz.3. 128. 2H).7. 7.6. 125. 7. 1H).0 Hz).1. 3H) ppm. 55. 1H). found: 334.30e7.0 Hz.57 (m.32 (m. 128.2.1.1. 149. 125. 123. (s.0. 1H) ppm.9.24 (m. 125. 13C NMR (400 MHz.58 (d. J¼4. 130. J¼8.43e7. 139. 1H).10 (m.4. LCeMS (EI): m/z calcd [Mþ1]þ¼316.57 (m.04 (s. CDCl3): 1H) ppm.0 Hz. 1H). 13C NMR (400 MHz. 1H). 1H NMR (400 MHz. 1H). CDCl3): d¼8.48 (m.5.0.1.6. J¼8. 7. 138.50 (m.28 (m.51 (m.2. 7.78 (m. 136.4 ppm.6.43e8. Gong et al. 7.69 (m. found: 350.10 (m. 7. 7. 4. 7.28 (m. 143.3.6. 113.11e7.3 (d. 150. 121.0.7. Mp 108e109  C. 139.2. 122.0 Hz. 136.4. J¼8. 1H).0.2. 2H). 4. 7.41 (m.49e7.0 Hz. 139.5.8.2.2 ppm. CDCl3): d¼8.6. 137.15 (m. 1H) ppm.5.73e7.78 (d. 3. 129.47 (m. 138.8. 13C NMR (400 MHz. 7. 125. 7. 1H).3.9.4 ppm. 1H) ppm.0 Hz.3. 1H).9. 2H). 136. LCeMS (EI): m/z calcd [Mþ1]þ¼350. 7.7.19 (t.1. found: 330. 2H). 143.8. 1H).0. J¼17. 2.3. 128.0.4 ppm.5. 1H).36 (m.0.6. 149.9. 4. 139. 7. 7. 139.9. 149. 3H).93e7. 129.34 (m.9.4. 1H). 7.3. 122. 7.0 Hz.1.53 (m.2. 1H). CDCl3): 2H).48e7.0. 122. CDCl3): methanone (3h).91 (d. 144.3.1. 137. 143. J¼8. 123. methanone (3j). 150. 1H). 143.45e7. CDCl3): d¼194. 7. d¼8.42 (m. 1H).34e7. 136.72e7.82e7. CDCl3): d¼195.95e7. 7. 132.2. 149.8. [Mþ1]þ¼392. 1H).0 Hz. J¼8. 151.41 (m. 1H). 132.6. 1H).0 Hz. 132.18e7.3.0. 139.60 (m. 143.48 (m.8. 149.2.1. CDCl3): d¼8. 150. 7. 1H).6. 123. 123. 4. J¼3.7 ppm.3. J¼4.4 (d. 2H).64 (d.7.58 (m. 4. CDCl3): d¼193. Mp 47e49  C.18e7. 1H).25e7.1. J¼8.3.3. 122. 1H).58 (d. 122.-J. 13C NMR (400 MHz.51e8. 2H).35 (m.1.5. LCeMS (EI): m/z calcd [Mþ1]þ¼346. (EI): m/z calcd [Mþ1]þ¼330.6.4. CDCl3): d¼180. 1H) ppm.5. 7.1. [Mþ1]þ¼334. J¼8.9. 150. 1H).46e7.0. found: 366.4. 6. .5. 128.62e7.0.2.86 (d. CDCl3): J¼254.0 Hz.45e7.9. 7. J¼8.5. 125.0 (d.9.7.90 (d. 152. 7. 125. 1H).4. 7. 123. 139. White solid.6.6.8.3.2. 7. 126. 7.4.1.0. 1H). Yellow solid.7.2. 2H). 125. (4-Fluorophenyl)(2-(pyridin-2-yl)benzo[b]thiophen-3-yl) methanone (3e). 139. 150. methanone (3k).92 (d.0 Hz. 123.7.3.5 ppm.0 Hz. CDCl3): 1H). 139.2.6.91 (m. LCeMS (EI): 122. 7. (m.56 (m.8.19e7. 136.07 (m. 136. 7.2. 2H).3. 1H) ppm.36e7. 136. 123.2.1. 125. 139. 130. 1H). 139. 151. J¼8.91e7. 149. 7.5. (4-Methoxyphenyl)(2-(pyridin-2-yl)benzo[b]thiophen-3-yl) methanone (3c).8. anone (3l). White solid. 2H). 1H).9. 7.0. 7.9.1.74 (d.0 Hz.5.3. 7.0 Hz. 113. 7. J¼8. Mp 137e138  C. 128. 136. 7.55e7. LCeMS (EI): m/z calcd [Mþ1]þ¼394. 122.0. 151. Yellow solid.30 (d.5.58e7.44 d¼8. 1H).0. 7. 132. 137. 7.0 Hz.8. [Mþ1]þ¼394. 7. 1H).6.11.5.3.9 (d. 1H NMR (400 MHz.31 (m. 136. 1H).5. 123.98 (m.5.7. 139. 130.54 (d.2.58e8. 7. 7. 1H NMR (400 MHz.9. Mp 117e119  C. 7. 3H) ppm.61 (t.5. 1H). J¼8.45e7.02 (m. Mp 146e147  C.6.2.09 (t.0 Hz.55 (m. 2H). 149.6.54e8. 125. 7. CDCl3): 125.57 (t. 125.18. 7.79 d¼194.88 (d.3. 123.36e7. 125.1H). 1H).0 Hz.6. 146. 127. 5H).70e7.49e7.6.1.3.8. 7. 147. CDCl3): d¼194. 123. 139. J¼4. 139. 149. 120.1.92 (d.41 (d. 133.1. 7. 13C NMR (400 MHz. 139.82 (d. 1H NMR (400 MHz.2.58e7.45e7. 7.9. 1H). 7. CDCl3): d¼8.2.5.4. Yellow solid. Mp 169e170  C. 2H). 153.2.2.0. 123. 124. 122. 2H). 7.0. 7.0 Hz.3.90 (m. 7.1.0 Hz. 13C NMR (400 MHz.91 (m.39 (m. CDCl3): J¼8.48 (m.64 (m.43e8.8. 123. 139.71 7. Yellow oil. (m. 1H). 136. 139.4 ppm. 139. (3-Bromophenyl)(2-(pyridin-2-yl)benzo[b]thiophen-3-yl) (5b).0 Hz. d¼186. 130. 13 C NMR (400 MHz. 1H) ppm. 125. 167. J¼8. 4. 122. d¼192. 123.65 (m. 123.67e7.3 ppm. CDCl3): d¼193.9.46 (m.2.33 (m.3.58e7.8.8. 1H). 149. 13C NMR J¼8. Mp 105e106  C.0 Hz. 2H). 8.14e7.9.0 Hz.9.2.45e7. 123. 132.2.3. found: 350.9. 143.7. 3H). 133. (m.1. 125. Mp 104e106  C.4. Mp 134e135  C.1.2.9. 1H).3. 1H NMR (400 MHz.11 (m. J¼4. 55.63e7.0.49 (m. 1H).65 (m. 13C NMR (400 MHz. 149.56 (m. 1H).7 ppm. 1H).4.6. 138. J¼8.00e7.10. 123.9. 139. 129. 6H).2. 125. 1H) ppm. 7. 2H).5.8.0. 1H).32e7. CDCl3): (400 MHz.0. 123. (2-(Pyridin-2-yl)benzo[b]thiophen-3-yl)(thiophen-2-yl)meth- CDCl3): d¼8.47e8. J¼8. CDCl3): d¼8. 131.9. 122. 3H). 144. (2-(Pyridin-2-yl)benzofuran-3-yl)(p-tolyl)methanone 4.15e7.63 (m. 139.48 (m. 7. J¼4. 131.92 (d. 128.57 (m. 139. methanone (3f).4. Mp 129e130  C.1.8.2.9. 149. 7. found: 306. J¼4. 124.9. 7.1H) ppm. 115. 1H). J¼4. (3-Methoxyphenyl)(2-(pyridin-2-yl)benzo[b]thiophen-3-yl) (3b).7. CDCl3): d¼194.1. 143.1.5.0. 13C NMR (400 MHz. 3H).40 J¼8. found: 322. 2H). m/z calcd [Mþ1]þ¼350. 1H). J¼8. 127. found: 300.7.64 (m. 7.2.0 Hz.6. LC-MS (EI): 123. 136. 7. 139. J¼8.64e7.3. CDCl3): d¼8.80 (s.9. 7. LCeMS (EI): m/z calcd m/z calcd [Mþ1]þ¼300. 132. 164.7.14e7. 7.2.54e7.5.0 Hz. 6. found: 346. 136. (4-Chlorophenyl)(2-(pyridin-2-yl)benzo[b]thiophen-3-yl) anone (3m). d¼8. 1H).0 Hz. 123.0 Hz.0 Hz.30 (m. 1H NMR (400 MHz.43 (m. 122. 1H). 3H). 151.7. 111. 128.58e8. CDCl3): methanone (3i). CDCl3): J¼8. 165.9.2.2. 126.54e7. 1H). 7.82 (d. 130.1.2. 1H).2.2. 125. 123. 7. 7. 123. 133. 7. 122. 7. 7.9. 130.34 (m.2.49e8. J¼8.1.80 (d. LCeMS (EI): m/z calcd d¼193.6. 3H). 7.0 Hz).0.63e7. J¼4. Yellow solid.0 Hz. 1H). Yellow solid.04 (m. 3H) ppm. 123.5. 1H). 129.1. 7. 7.45e7. 122. found: 392. 7.16 (d.93e6.00e7. 122.0 Hz. 122. (m. 7.0 Hz). 133.0.63 (d.16. 144.43e7. 7.0. 6.0 Hz. LCeMS (EI): m/z calcd [Mþ1]þ¼366. 132.5. 1H).8.49 (m.46e7. 132.14e7. 123.13e7. 1H). 143.0. Yellow solid.4. 122. 138. J¼10.1. 21. 122.08 (m. 122. 128.98 7. 125. d¼193. (Furan-2-yl)(2-(pyridin-2-yl)benzo[b]thiophen-3-yl)meth- 4. [1.6. 7.0 Hz).27 (m. 4.0 Hz. found: 316. Yellow solid. / Tetrahedron 71 (2015) 1269e1275 1273 7. 122. 4.49 (m.65 (d. (2-Chlorophenyl)(2-(pyridin-2-yl)benzo[b]thiophen-3-yl) CDCl3): d¼8.4.07e7.3. Yellow solid.22e7. 7. 3H). 133.17.4. 1H). 7. 1H NMR (400 MHz. 7. 133. 7. 1H). 7.

06e7. 13C NMR (400 MHz. (m.0 Hz. 133.2. 7. 111.0 Hz. 118. Yellow solid. 13C NMR (400 MHz.1.58 (m.70 (m.8. 123. 7. CDCl3): d¼178.36 (m.0 Hz. 7.33 (m. 7.0 Hz). 1H).8. 123.5.5.0 Hz). 7.0. 7.23. CDCl3): d¼8. 7. J¼8. 149. 147.0 Hz.0 Hz.14 (m. J¼8.9. [1. J¼8.2. 129.9. 1H). 7. 1H). (5m). Education Institutions. 7. mentary data associated with this article can be found in the online anone (5i). 139.7. 144. 149. 121.1. m/z calcd [Mþ1]þ¼350.8.3.8. 165.9.0.4.65 (m.2. (4-Methoxyphenyl)(2-(pyridin-2-yl)benzofuran-3-yl)meth- anone (5c).45e7. 1H).17e7. ences (2015kf-07). 123. 124. 7. CDCl3): 4.45 (m. found: 314.0 Hz).87e7. J¼8. 1H). 1H). 21.31e7.71 (t. Yellow solid.40 (m.2014. 134.6. 136.0 Hz.doi.2.2. 21171125. 123. found: 330. 149. 1H).7. 7.1. 1H).1. 1H). 122.73e7.63 (d.05e8. 122.41 J¼253. The authors also thank the useful suggestions 7. 4.37 (m.4. Supple- 4. 112. 55.5.0 Hz. Acknowledgements 7. 128.9.0. 149. (t. 1H).1.6. 1H). 128. 7. 136. 7. 147. LCeMS (EI): m/z calcd [Mþ1]þ¼306. 149. 128.62 (m. 136.2. 1H). 136. Mp 147e149  C. J¼8. 124. J¼8.56 (m.5 (d. and the ‘SooChow Scholar’ Program of CDCl3): d¼8. 148.7. 154.7.19 (m. 1H). 136.6.2. at http://dx.2. 124.0 Hz.3.86 (m.10 -Biphenyl](2-(pyridin-2-yl)benzofuran-3-yl)methanone (5d). J¼8.2. 1H). 123. 7.29 (m.48 (m.7.2. 124.29 (m. 1H). 147. 126.1274 W.41 (t.2. 118.18.1.6.8.8. 124. 7. 1H). 124.55 (m.25 CDCl3): d¼8. 1H).15 (m. 136.1. 1H). 1H).8.63 (d.17e7. J¼4. Mp 103e104  C. 1H).20e7. 148.8.0.47 (br s.39 (m.46e8. 13C NMR (400 MHz. LCeMS (EI): m/z calcd [Mþ1]þ¼334. 1H) ppm. 1H). 7. 122. 147.7. 2H). 122.83 (s. 13C NMR (400 MHz. (Naphthalen-2-yl)(2-(pyridin-2-yl)benzofuran-3-yl)meth- d¼8. Yellow solid. CDCl3): d¼184.3. 7. 128.21e7. (5l). 55. CDCl3): d¼8. J¼8. 124. 7. 147. 113.2. 1H).1. 5H).4.4.85 (d.79 (d.23e7. 154.7.7. 2H). 120.49 (m.27.4. 124.28 (m. anone (5j). 154.0 Hz.2.1. 1H).0.0. 7. 111. anone (5k).7. 115.7. 7. 1H). 153. 1H) ppm.88e8.37 (s. 132. 7.88e7.7. 113. 7.26 (m.4.5. 2H). 152.45e7.0. 147.tet.3. 111.0. 7. 147. 121.3. 122.1.2.83 (m.3. 136.0.50e7.68e7. 1H). 7.1. The authors thank the financial supports from the National J¼4. CDCl3): d¼190.18. 7.5. 111.7 (d.6.2. (m.0 Hz.0 Hz. 7. 121. J¼8.0.30 (m.38e8. J¼22.84 7.0 Hz. [Mþ1]þ¼314.19 (m. Yellow solid. 1H).40 (m.70e7. 136.62 (d.2.2.42e7.7 ppm.91 (m. LCeMS (EI): m/z calcd [Mþ1]þ¼378. 1H NMR (400 MHz. 1H). 13C NMR (400 MHz. 1H).1. (2-Chlorophenyl)(2-(pyridin-2-yl)benzofuran-3-yl)meth- d¼8. 127. 7.30 (m. 123. CDCl3): d¼8. CDCl3): 1H). 1H).9. 2H). 154. 6. 7. 148.9.54 (m. 1H). 122. 7.9.8. Yellow oil.7 ppm. 13C NMR (400 MHz. 126. J¼8.6.4. Shanghai Institute of Organic Chemistry.0. 156. 152. 7.7 ppm. 111. 121.0. 1H).2. (2-(Pyridin-2-yl)benzofuran-3-yl)(thiophen-2-yl)methanone 1H).15 (m. 1H) ppm.0.0 Hz.74e7. CDCl3): d¼190.55 (d. 1H NMR (400 MHz. version. 154. 121. 7.41e7. 7.0 Hz. 7. 121. 7.3. 137. J¼8.22.8.3. 111.5.3. 132. J¼4.2.59e7.-J. 1H) ppm. 139. found: 334. 1H). 7.69 (m.9.0 Hz.33e7.095. 7. 149. 1H). 7.19. 126.L.55 (m. and 153.9.5. J. Supplementary data LC-MS (EI): m/z calcd [Mþ1]þ¼378.53e8.40 (m.28e7.0. 129.45 (m.70 (t.0.3.64 (m.1. 7. 130.89 (d. 7.0.4.0 Hz. 8.4. 7. 1H).4.4.6.7 ppm.95e7. (4-Fluorophenyl)(2-(pyridin-2-yl)benzofuran-3-yl)meth.8.40 1H). LCeMS (EI): m/z calcd 4. 126. 116.3.46 (m.25e7. 139.8. 7. 1H NMR (400 MHz.8. 159. mp 143e144  C.7 ppm. 1H NMR (400 MHz. 1H). 1H).62e7. 128.12e8. 128.9. 140.3.17e7. 126.58e7. 128. 7. CDCl3): d¼8. 2H).93e7. d¼191.7. LCeMS (EI): m/z calcd [Mþ1]þ¼376. 128. Mp 160e162  C. found: 350. 1H). J¼8. 1H). LCeMS (EI): m/z calcd [Mþ1]þ¼318.0. 123.0 Hz. 1H NMR (400 MHz. 153. 149.59 (d. 7. 1H).3. 7. 126. 1H).1.42e7. 134.0 Hz. 1H). 124. 7. highly appreciates the financial supports from the Qin-Lan Project and the ‘333’ Project of Jiangsu Province.0. 111.21. 122. 129.47e7. 127. 134. 7. J¼8.65e7.0 Hz.4. 153.5 ppm. found: 318. 7.7 ppm. 139.4.06 (m.3.7.60 (m.6.72 (t. 1H) ppm. found: 306. 13C NMR (400 MHz.55 (d.2. 154. 1H). 7.1.0 Hz).3.2.6 ppm.4. CDCl3): d¼191.7. 7. 126.9.0 Hz. 131. 1H). 127.1. J¼8.6. Gong et al.9.27e7. 7. The 1H and 13C NMR spectra for the isolated products.1. 1H NMR (400 MHz.2.2. J¼8. 126. J¼4. (m. (d.4.69 1H).9.86 (d.8. 1H).2. 137.52 (s. 154.30 (m.67 (m. 136.49e7.8. 3H). 1H). 121.71e7. 1H). CDCl3): 123.04 (m. J¼8. 1H NMR (400 MHz. 7.4.63 (d.70 (t.1. 154.33e7.8. 119. J¼8.1.8. J¼8. 111.2. m/z calcd [Mþ1]þ¼330. 147.0.7. 130. 1H).5. 119.12.8. 136. 121. 127. 126. 135. 13C 128.36 (m.5. 3H) ppm. (EI): m/z calcd [Mþ1]þ¼334. 154.00e6.1. (3-Bromophenyl)(2-(pyridin-2-yl)benzofuran-3-yl)meth- the Priority Academic Program Development of Jiangsu Higher anone (5h).44e8. 1H). J¼8. 122. 128.87e6. J¼8. Soochow University.2. 7.2. 149. 127.2. CDCl3): d¼191. 1H).2. Yellow solid.19 (t.29 (m. 131. J¼8.1. LCeMS (EI): d¼190.1. 6. CDCl3): 1H).31e7.16 (t. 7.41 (t. 154.0 Hz. J¼8.5.3.5. 153.9. 7. 136.5. Mp 129e130  C. Yellow solid. 8. 131. 126. 119.28. 149.2. 147. 7. 7. Yellow solid. 121. 7. 1H).2. 149. 7. Furan-2-yl(2-(pyridin-2-yl)benzofuran-3-yl)methanone CDCl3): d¼8.81 (m.1.2.2.9. J¼4.0 Hz.44 (br s. 113.70e7.8.11 (m. 3H). 153. 3H). 1H).04 (m.8 ppm. 137. 7.4. 2H).24 (m.2. 123. 4.97 (m. 126. / Tetrahedron 71 (2015) 1269e1275 7.8. 117.76e7. 130. 132. 126. 2H). 7.86 (m.1.5.2.0 Hz. 7.63 (m.6.33e7.7.37 (br. 152.0 Hz. 121. 7.31e7. 154.83 (d. LCeMS (EI): 4.6. Mp 112e114  C.9.0 Hz. LCeMS (EI): m/z calcd CDCl3): d¼192.1. 1H).41 (t. (4-Bromophenyl)(2-(pyridin-2-yl)benzofuran-3-yl)meth. 7.26. CDCl3): d¼193. 7.4.5 1H) ppm. J¼4.4.7.3.2.8. 1H). 123. 1H).1. 117. (m. 7. 119. 7. 7.6.1e8. 7. 145. 128.2. (m. 149.43 (t.2.0 Hz. 1H).64 (d.7 ppm. 146.2. 123. 7. (4-Chlorophenyl)(2-(pyridin-2-yl)benzofuran-3-yl)meth- anone (5f).1 (d. found: 376. found: 334. 123. 1H).77 (t. 2H). 130. J¼8. 128. 1H). found: 290.57e7. (d. 2H).0. 7. 1H).1. 1H). 3H).39 (m. 4. 21371126) and State Key Laboratory of Organometallic Chemistry. 1H) ppm. Yellow solid. 154.36e7.00e6. 111. 7.32e7. 1H NMR (400 MHz.19e7.7. 7.13 (t. 3H) ppm. found: 330. 1H).27e7. 4.0 Hz. 128.25. Mp 44e45  C.22e7.52 (m. 2H). 111. 13C NMR (400 MHz.41 (m. Mp 151e152  C.86 (m.20.4 ppm. 13C NMR (400 MHz. 121. 7.1. 155. J¼8.40e8.0. CDCl3): 2H).2.1. 4H).0 Hz.4. 3. J¼8. 117.43 (m. 123. 126.2.0 Hz. 7.3.91 (m.13 (m.0 Hz.5.49 (d.4. found: 378. 130. 5H). d¼8.14 (m. NMR (400 MHz. 1H NMR (400 MHz. anone (5e). 121. 7. 111. 128.24 (m.2.2. 1H).1.org/10. 1H).8. 124. 1H). 1H). 117.43e7. 121. 1H). 122.0. 7.98 (m. 136.0 Hz. LCeMS (EI): m/z calcd [Mþ1]þ¼330. 7. 4.1. LCeMS 1H).87e7.26 of the editor and the reviewers. 2H).56e7. 7. 120.2. 13C NMR (400 MHz.25 (m.1. 4. 121.9.5.24. 7.83e7. J¼8. 132. J¼8. J¼9. Yellow solid. (t.1.1. (3-Methoxyphenyl)(2-(pyridin-2-yl)benzofuran-3-yl)meth.7. 1H). 7.25 (m.31e7.91 (d. 7.46e8. 127. 13C NMR (400 MHz.22e7.6.-P. . 124.1.4. 2. 147.1016/j. Mp 116e118  C. 132.5. 129. 129.9.0. 7. 1H NMR (400 MHz.7. 7.7 ppm. 123. 122.02 d¼8. 130.60e8. Chinese Academy of Sci- found: 378. 123. 7. 153. 2H).37e8.87 (d.9. 1H).0 Hz.76 (d. CDCl3): 4.98 (d.0 Hz.1. 126. [Mþ1]þ¼290. 7.4. J¼3. 7. 118.3. 144. 154.2. 1H) ppm.4.9. 7. 2H) ppm.2.7. Yellow solid. CDCl3): d¼191. 119.1.16 (m.65 (d.58 (m.31e7. 2H).2. 1H). 136.33e7.5. J¼8. 1H). mp 133e134  C. Natural Science Foundation of China (21171124.07e7. 126. 135. 2H) ppm. 1H).1.3. 1H). 7.0. 1H NMR (400 MHz.0 Hz.0.7. anone (5g).2. 7.0 Hz. J¼4. CDCl3): d¼190.3.2.86 (d.17 163.

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