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DOI: 10.1002/chem.201101992

Dehydrogenative Heck Reaction of Furans and Thiophenes with Styrenes under Mild Conditions and Influence of the Oxidizing Agent on the Reaction Rate
Alexandre Vasseur, Jacques Muzart, and Jean Le Bras*[a]
Transition-metal-catalyzed reactions dealing with CÀH activation is a challenging task in organic chemistry.[1] The Pdcatalyzed couplings of arenes with alkenes through CÀH activation, also called intermolecular dehydrogenative Heck reactions (DHRs), have gained interest these past years.[2] Despite noticeable progresses, the substrate scope is often limited to olefins bearing an electron-withdrawing group as the coupling partner, which limits the applications of these reactions. We have recently reported an efficient method for the coupling of furans with styrenes, which allowed the use of chlorinated and fluorinated substrates.[3] However, brominated substrates were reluctant to react. These compounds would allow the synthesis of valuable products for further functionalization through other cross-coupling reactions. Glorius et al. have recently shown that brominated compounds can be formed with no proto-debromination using Rh catalysts; however few examples have been reported and the scope of substrates remains to be developed.[4] A recent example has been reported by Zhang et al. using palladium catalysts, but the method requires the presence of a removable pyridylsulfinyl group on the arenes.[5] Among the arenes used in DHRs, furans and thiophenes have received little attention. The former are acid sensitive and the latter require elevated temperatures,[6] due to their higher aromatic resonance energy and stability.[7] We report herein the DHRs, under mild conditions, of furans and thiophenes with styrenes, including brominated substrates. The influence and the role of the oxidizing agent on the activity of the catalyst are also discussed. We noticed an induction period during our previous study that depends on the nature of the furan, the transformation being faster with electron-rich furans.[3] We also observed that the solvent can have a decisive influence on the course of the reaction. Low-coordinating solvents led to Heck-type products,[3] whereas coordinating solvents gave difurylalkanes.[8] We have pursued our investigations on the influ[a] A. Vasseur, Dr. J. Muzart, Dr. J. Le Bras Institut de Chimie MolØculaire de Reims-UMR 6229 CNRS-UniversitØ de Reims Champagne-Ardenne UFR des Sciences Exactes et Naturelles BP 1039, 51687 REIMS Cedex 2 (France) Fax: (+ 33) 3-26-91-31-66 E-mail: jean.lebras@univ-reims.fr Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201101992.

ence of the solvent on the DHR of heterocycles with styrenes. The coupling of 2-methylfuran (1 a) and 2-methylthiophene (1 b) with styrene (2 a) has been studied at room temperature over 4 h, in the presence of PdACHTUNGRE(OAc)2 as catalyst, benzoquinone (BQ) as oxidizing agent, AcOH as solvent, and a series of co-solvents (Table 1). The reaction was generally ineffective (Table 1, entries 1–7). Only DMSO strongly improved the efficiency of the reaction leading to 3 aa in 64 % isolated yield (Table 1, entry 8). This is a surprising result since DMSO is a coordinating solvent, and we expected the formation of difurylalkanes under such conditions.[8] Interestingly, 2-methylthiophene (1 b) could also be coupled with 2 a in 58 % yield at room temperature over 4 h (Table 1, entry 9). The yield of 3 ba was increased to 67 % when the reaction time was prolonged to 24 h (Table 1, entry 10). This is an interesting improvement, since reported methods for the DHR of thiophenes require 60–120 8C and are limited to olefins bearing an electron-withdrawing group.[6] The use of catalytic amounts of BQ and CuII in association with O2 reduced the yield of 3 ba (Table 1, entry 11). The scope of the process was then examined (Table 2). After slight modifications to the original proceTable 1. Optimization of the coupling of 2-methylfuran (1 a) and 2-methylthiophene (1 b) with styrene (2 a).[a]

Entry 1 2 3 4 5 6 7 8 9 10[c] 11[d]

1 1a 1a 1a 1a 1a 1a 1a 1a 1b 1b 1b

Co-solvent Et2O CF3CH2OH MeOH tBuOH CH2Cl2 DMF DMA DMSO DMSO DMSO DMSO

3 [%][b] 11 8 8 9 11 9 8 67 (64) 58 (67) 45

[a] 1 (2.0 mmol), 2 a (1.0 mmol), PdACHTUNGRE(OAc)2 (0.05 mmol), BQ (2.0 mmol), AcOH (2 mL), co-solvent (2 mL), RT, 4 h. [b] GC yield, isolated yield in parenthesis. [c] The reaction was performed over 24 h. [d] BQ (0.5 equiv), CuACHTUNGRE(OAc)2 (0.1 equiv), O2 (gas bag) instead of BQ (2.0 mmol), 24 h.

Chem. Eur. J. 2011, 00, 0 – 0 

2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

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[b] Isolated product yield. 0 – 0 ÝÝ These are not the final page numbers! . Weinheim Chem. 2 (1 mmol). RT. &2& www. KGaA.[a] Entry 1 2 Pd [%] 5 t [h] 24 3 [%][b] Entry 1 2 Pd [%] 5 t [h] 24 3 [%][b] 1 1c 2a 3 ca 68 14 1b 2b 3 bb 90 2 1d 2a 5 24 3 da 79 15 1b 2c 5 24 3 bc 56 3[c] 1e 2a 5 48 3 ea 40 16 1h 2b 10 24 3 hb 56 4 1f 2a 5 24 3 fa 78 17 1h 2c 5 24 3 hc 68 5 1a 2b 5 24 3 ab 73 18 1i 2a 5 48 3 ia 72 6 1d 2b 5 24 3 db 61 19 1i 2d 5 48 3 id 88 7[d] 1g 2a 5 24 3 ga 54 20 1i 2e 5 48 3 ie 92 8[d] 1g 2b 10 48 3 gb 40 21 1i 2b 5 48 3 ib 65 9 1h 2a 5 24 3 ha 72 22 1j 2a 10 48 3 ja 77 10 1b 2d 5 24 3 bd 97 23 1j 2d 10 48 3 jd 76 11 1b 2e 5 24 3 be 59 24 1j 2b 10 48 3 jb 56 12 1h 2d 5 24 3 hd 70 25 1j 2c 10 48 3 jc 57 13 1h 2e 5 24 3 he 80 [a] 1 (2 mmol). Eur. 0000. DMSO (2 mL). Coupling of furans and thiophenes 1 with styrenes 2. conv.Table 2. 24–48 h. AcOH (2 mL). [d] 1 g (5. 100 %.chemeurj.0 mmol). J. [c] Reaction performed at 40 8C. 00. BQ (2 mmol).org  2011 Wiley-VCH Verlag GmbH & Co.

0 mmol).0).0 mmol). RT. As previously observed. To learn about the CÀH activation step. 6. We have therefore performed kinetic experiments to determine the role of BQ in the mechanism. DMSO can act as a ligand to give the monomeric palladium complex A (Scheme 1). and all compounds were obtained as the E isomer. the method is compatible with brominated styrenes and furans (Table 2. entries 5.[10] The coupling of 1 b with 2 a has shown that the oxidizing agent has an influence on the yield of the reaction (Table 1. This effect was however not observed when tert- Figure 3.[3] 2-substituted furans bearing either an electron-donating group (Table 2.1 equiv). 2-Alkylthiophenes were coupled with various chlorinated and brominated styrenes (Table 2. Furthermore.0 mmol). Dependence of the yield of 3 aa on [BQ]. showing that BQ has no influence on the CÀH activation. entry 11). 2 a (1. O2 (1 atm). furfuryl alcohol 1 f. 00.0 equiv of BQ had a negative impact on the rate of the formation of 3 aa after the initial stage of the reaction (Figure 3). J. DMSO (2 mL). the use of 1. entry 1) or an electron-withdrawing group (entry 3) reacted at the C5 position. RT. & = BQ (1 equiv). Kinetic isotope effect. The induction period observed in a mixture of Et2O/AcOH as solvent was attributed to the complexation of the catalytic trimer [PdACHTUNGRE(OAc)2]3 by furan leading to the dimeric or monomeric Pd active species. BQ (2. Conditions: PdACHTUNGRE(OAc)2 (0. have shown that after the CÀH activation of arenes by PdACHTUNGRE(OAc)2. entry 4). 2 a (1.5 equiv of BQ and 0. 2 a (1. Interestingly. The kinetic of the coupling of 1 b with 2 a was monitored by GC using 1. Some reactions required 10 % catalyst loading to achieve a total conversion of 2. entries 10–17).0 equiv of BQ has however a small effect on the rate after the initial stage of the reaction.[11] Computational studies by Sakaki et al. we performed a kinetic study with 1 b and monodeuterated thiophene d-1 b (Figure 1). Halogenated thiophenes are precursors for the synthesis of oligothiophene-based materials. The reactions were performed at RT. entries 19–21 and 23–25). The syntheses of 3 jb and 3 jc could be performed in similar yields at 40 8C over 24 h. 0 – 0  2011 Wiley-VCH Verlag GmbH & Co. except in the case of 1 e. AcOH (2 mL).org &3& These are not the final page numbers! ÞÞ . RT.05 mmol). AcOH (2 mL).0 and 2. CuACHTUNGRE(OAc)2 (0. 2011. Dependence of the yield of 3 ba on [BQ]. It should be noted that no trace of furfural or furoic acid were detected by GC.Dehydrogenative Heck Reaction COMMUNICATION dure.0 mmol). and 8). AcOH (2 mL).5 equiv).chemeurj. DMSO (2 mL). chlorinated and brominated thiophenes also react at room temperature with halogenated styrenes in fair yields but require a longer reaction time (Table 2. Interestingly.0 mmol). For the coupling of furan 1 a with 2 a. showing that the method is highly selective towards the CÀH activation.1 equiv of CuACHTUNGRE(OAc)2 has a stronger impact. KGaA. which is consistent with a mechanism involving a Pd-mediated CÀH cleavage step rather than a Lewis acid-mediated Friedel–Crafts reaction. Weinheim www. Figure 1.0 mmol). 1 (2. Figure 2.[9] therefore the method provides a new entry for the synthesis of such molecules under mild conditions. Conditions: PdACHTUNGRE(OAc)2 (0. & = BQ (1 equiv). DMSO (2 mL).0 equiv of BQ (Figure 2). The initial rate was unchanged.05 mmol). Working with 1. furans and thiophenes were successfully coupled with styrenes to give Heck-type products in medium to good yields. A significant isotope effect was observed (kH/D = 4.05 mmol). Indeed. The use of O2 with 0.[3] We did not observe any induction period using a DMSO/AcOH mixture. butyl acrylate (2 f) was used instead of 2 a (Figure 4). was successfully coupled without the need of a protection of the alcohol function (Table 2. ^ = BQ (2 equiv). ~ = BQ (0.0 mmol). Eur. the palladium center in the resulting ArPdOAc is more elec- Chem. Conditions: PdACHTUNGRE(OAc)2 (0. 1 b (2. ^ = BQ (2 equiv). 1 a (2.

Compound 3 was isolated from purification by flash chromatography (SiO2. insertion of the C= C bond into the ArÀPd bond is followed by a b-H elimination leading to 3 and the reoxidation of palladium. an electron-poor benzoquinone should facilitate the interaction of C with 2. which is more susceptible to coordinate the electron-rich styrenes than ArPdOAcACHTUNGRE(DMSO)2. Conclusion Furans and thiophenes were coupled with styrenes through CÀH activation under mild conditions. The mixture was stirred at room temperature for 24– 48 h. showing that 2 a is more prone than BQ to perform an insertion Experimental Section General procedure for the coupling of 1 with 2: A round bottom flask was charged with BQ (216. Conditions: PdACHTUNGRE(OAc)2 (0.0 mmol). DMSO (2 mL).0 mmol). Eur. reaction. We have performed a classical Heck reaction using BQ (1.0 mmol) in the presence of methyl 4-iodobenzoate (1. Weinheim Chem. Dependence of the yield of 3 af on [BQ]. ^ = BQ (2 equiv). PPh3 (0.0 mmol). & = 2Cl-BQ (1 equiv). such as 2 f. Compared with the previously reported RhIII-catalyzed reactions. We suspect that the formation of D is faster than the insertion of BQ into the PdÀAr bond of C. 00. PdACHTUNGRE(OAc)2 (11. It should be noted that C or D could lead to the insertion of BQ into the PdÀAr bond. 2 f (1. Finally. which requires the presence of BQ for the coordination of styrenes. AcOH (2 mL). The differences observed on the effect of BQ between Figures 2 and 3 are due to the fact that 1 a is more nucleophilic than 1 b. Only (E)-methyl 4-styrylbenzoate was observed. complex D probably evolves as proposed in Scheme 1. including brominated thiophenes and styrenes. which is less electron-rich than B. would interact directly with B.0 mmol). we have observed that the reaction of 1 a with 2 a is more efficient in the presence of one equivalent of 2-chlorobenzoquinone than one equivalent of BQ (Figure 5). 2 a (1. petroleum ether 100 % or petroleum ether/EtOAc. Le Bras et al. AcOH (2 mL). Scheme 1. Electron-poor alkenes. Therefore. & = BQ (1 equiv). The resulting complex C.0–5.05 mmol). and then evaporated to dryness.2 mg. ^ = BQ (1 equiv).05 mmol). From D. Dependence of the yield of 3 aa on the nature of the oxidant. 98:2–70:30). 0000.0 mmol). 20 mL) and H2O (20 mL). AcOH (2. this method is advantageous with a wider scope of substrates and cost-effective PdII catalysts.2–22.0 mL). DMSO and benzoquinone have an influence on the efficiency of the process. J.0 mmol).05–0. whereas benzoquinone interacts with the ArPdOAcACHTUNGRE(DMSO)2 intermediate to give the less electronrich species ArPdOAc(BQ)ACHTUNGRE(DMSO). DMSO (2 mL). The organic phase was washed with NaOH (2 m. Conditions: PdACHTUNGRE(OAc)2 (0. DMSO (2.0 mmol). PdACHTUNGRE(OAc)2 (0. 1 a (2.05 mmol). RT. Proposed catalytic cycle. 0 – 0 ÝÝ These are not the final page numbers! . The combined organic phases were dried over MgSO4.chemeurj. It is proposed that DMSO acts as a ligand. 0. The combined aqueous phases were extracted with Et2O (20 mL). 2. Figure 5. interacts with electronrich styrenes 2 a–e leading to D.4 mg. and would be less sensitive to the amount of BQ.0 mmol) and 2 a (1.J. tron-rich than in PdACHTUNGRE(OAc)2. Et2O (20 mL) was then added. &4& www. 1 a (2.0 mmol).4 mmol) in THF.org  2011 Wiley-VCH Verlag GmbH & Co. A saturated aqueous solution of NaHCO3 (20 mL) was then slowly added with rapid stirring. and can easily coordinate BQ. 1 (2. Figure 4. which would interact with BQ. Indeed.[13] and probably leads to an electron-rich B.0 mmol) and 2 (1.25 mmol) and NEt3 (1.1 mmol). RT. KGaA.[12] We propose that CÀH activation of 1 by A leads to B. The method is compatible with halogenated substrates.

[12] A. Curr. Top. 1221 – 1226. 2011. 2758 – 2761. Lett. Perepichka). Baudoin. Received: June 28. 195 – 209. 2010. l) C. f) G. Arrayµs. C. 2010. 2010. García-Rubia. J. 16. Y. V. 540 – 548. 5. 6019 – 6028. [13] H. Coord. e) K. B. Rev. Org. Ofial. Ca’. J. 2011 Published online: && &&. M. Am. Besset. 2003. 1315 – 1345. P. Ackermann. C. Chem. Renaudat. Scheuermann. 2009. 2009. Motti.chemeurj. 2010. 2010. F. Ashenhurst. M. 39. Le Bras. Chiusoli. J. 3279 – 3289. see: a) L. T. Mayr. D. Chem. Synthesis 2011. Top. Y. 2010. L. Muzart. Chem. J. Acc. 2011. N. Organometallics 2005. 2530 – 2539. Muzart. 3996 – 4004. 82. 76. Res. Org. Chem. J. M. K.-J. 111. Synthesis 2011. You. 1147 – 1169. Tetrahedron 2008. Tani. D. Zhao. c) T. A. 456 – 469. Costa. Aouf. J. 2011. m) C. Li. [10] Electrophilic aromatic-type substitutions lead to lower values of kH/D. Huang. j) S. Urones. 2011. 36. Sato. Dong. Carretero.-L. 2010. V. R. H. 111. Mills. Vols. Chem. W.: I. Zierkiewicz. Satoh. Privalov. Chem. 335 – 344. New York. 64. B. Rossi. 42. Sureshkumar. 50. 1403 – 1413. J. J. Le Bras. Soc. 353 – 369.Dehydrogenative Heck Reaction COMMUNICATION [2] J. Chem. New York. J. Rev. Res. A. Asian J. C. [7] J. Eur. c) M. 5th ed. 2011. Shi. o) R. Bellina. Joule. 1082 – 1146. [3] C. Top. Curr. R. 24. Am. 1170 – 1214. p) G. Rev. Ishii. Chem. M. J. 133. de Haro. Nakao. Chem. Chem. b) C. 2010. 292. Chem. studentship to A. 5982 – 5986. Chem. Thiery. T. Patureau. 292. 2654 – 2672. 00. Chem. 66 – 77. T. Weinheim www. Le Bras. 123 – 164. 2010. Dalton Trans. Y. Glorius. F. 110. F.. Eur. Cheng. O. Chem. n) T. 2011 Acknowledgements We are indebted to RØgion Champagne-Ardenne and CNRS for a Ph. Liang. A. 9676 – 9685 and references therein. see: a) J. b) F. [9] Handbook of Thiophene-Based Materials: Applications in Organic Electronics and Photonics. Beck. d) M. 11. J. Zhang. 2010. Klussmann. Sanford. 0 – 0  2011 Wiley-VCH Verlag GmbH & Co. i) F. 2009. Curr. 1215 – 1292. Top. Maehara. 4987 – 4994. Jazzar. 292. Chem. Miura. S. Wang. q) F. Catellani. Kempf. D. Chem. 4096 – 4099. 2010. 2011. Heterocyclic Chemistry. 69. h) E. Z. 2009. Wu. Maestri. 165 – 194. [6] For the DHR of thiophenes. Rev. Rev. Y. Nevado. 294 – 307. Tetrahedron Lett. Acc. Miura.D. k) L. M. 2010. [11] W. KGaA. Chem. E. 57 – 84. Keywords: CÀH activation · dehydrogenation · furans · Heck reaction · palladium · thiophenes [1] For selected recent reviews. Chem. Hitce. Rev. J. 110. Organometallics 2008. 2010. 436 – 451. Soc. M. A. S. Top. Xia. Chem. Larock. Yeung. Perepichka. Chem. see: A. D. J. J. 111. Glorius. Harakat. Soc. b) A. R. Rev. [4] a) S. 2010. Y. 9982 – 9983. r) J.org &5& These are not the final page numbers! ÞÞ . J. and for financial support. Pure Appl. Rakshit. 85 – 121. Wiley. Grohmann. Gaunt. 2004. 2010. K. Chem. g) O. 16. E. J. S. Chem. Liu. Eur. Lyons. C. R. Curr. F. [5] M. Wiley. Thiery. G. 2350 – 2353. 254. 1 and 2 (Eds. S. M. [8] E. 2010. Y. Muzart. Daugulis. J. Sofack-Kreutzer. 292. Ishikawa. Chem. Sakaguchi. 39. 292. Zhang. 132. Curr. Ackermann. 27. Sakaki. J. Yu.-B. Hirano. Synlett 2011. M. Org.

Weinheim Chem. This method allows the coupling of brominated substrates through CÀH bond activation. 00. . CÀBr in Heck: The direct dehydrogenative coupling of furans and thiophenes with styrenes occurs under mild conditions (see scheme). Vasseur. . Le Bras* .org  2011 Wiley-VCH Verlag GmbH & Co. J. &&&&—&&&& Dehydrogenative Heck Reaction of Furans and Thiophenes with Styrenes under Mild Conditions and Influence of the Oxidizing Agent on the Reaction Rate CÀH vs. J. J. . In addition. . . DMSO and benzoquinone had a positive effect on the reaction rate. .chemeurj. 0000. KGaA. . .J. 0 – 0 ÝÝ These are not the final page numbers! . . . Le Bras et al. . . . . . . &6& www. . . Heck Reaction A. . Eur. Muzart.