DOI: 10.1002/chem.201302962
Aerobic Oxidative Coupling between Carbon Nucleophiles and Allylic Alcohols: A Strategy to Construct b-(Hetero)Aryl Ketones and Aldehydes through Hydrogen Migration Liangbin Huang, Ji Qi, Xia Wu, Wanqing Wu, and Huanfeng Jiang*[a] Since the early 1970s, the Pd-catalyzed Heck reaction has become a powerful tool to prepare substituted olefins.[1, 2] The main challenges in the intermolecular Heck reaction are controlling the regioselectivity and high selective b-H elimination when olefins without a significant electronic difference at the two olefinic sites are used as the substrates.[3] The groups of Stahl and Zhou recently reported ligand-controlled regioselectivity in the synthesis substituted olefins through Heck-type coupling of alkenes with vinylboronic acids and aryl triflates.[3f, 4] To solve the problem of selective b-H elimination, Sigman and co-workers designed palladium catalysts that were capable of distinguishing C H bonds on the basis of relative bond strength.[5] Jiao found that b-H elimination is highly chemoselectively controlled in a ligandfree system when allyl esters reacted with carbon electrophiles or carbon nucleophiles, due to chelation between O and Pd atoms.[6] Lei and Nacci achieved the highly selective arylation of allyl alcohols through redox-neutral pathway with iodobenzene or the oxidative approach with benzoboric acid, respectively. [Eq. (1)].[7] Recently, Pd-catalyzed oxidative coupling between benzoic acids and allyl alcohols leading to b-aryl ketones was reported.[8] However, some drawbacks of this method may limit its application. Firstly, the
[a] L. Huang, J. Qi, X. Wu, W. Wu, Prof. Dr. H. Jiang School of Chemistry and Chemical Engineering South China University of Technology Guangzhou 510640 (P. R. China) E-mail: [email protected] Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201302962.
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substrate scope is limited to ortho-substituted benzoic acids. Secondly, stoichiometric amounts of Ag salts were used as the oxidant. Herein, we present a palladium-catalyzed aerobic oxidative coupling of allylic alcohols with (hetero)aryl nucleophiles to construct b-(hetero)aryl ketones and aldehydes. Recently, increasing interest has been focused on PdII-catalyzed C H activation[9] and decarboxylation,[10] including its derivatives of carboxylate variants,[11] instead of Ar X (X = halide, OTf and metal; Tf = triflate) for cross-coupling reactions. They provided complementary approaches for obtaining carbon nucleophiles. On one hand, arylsulfonyl hydrazides are cheap and readily available carbon nucleophiles used for oxidative cross-coupling reactions. On the other hand, (hetero)arene derivatives are of great importance as building blocks for pharmaceuticals and bioactive compounds. Evidently, the direct utilization of allyl alcohols coupling with those carbon nucleophiles to obtain b-(hetero)ACHTUNGREaryl ketones and aldehydes by using oxygen as the sole oxidant would be a fascinating approach [Eq. (2)]. In addition, the frequently used strategies for C H bond alkylation are the hydroarylation of alkenes as well as direct alkylation with alkyl halides. The oxidative coupling between (hetero)arene and allyl alcohols provides an alternative approach for C H alkylation.[12] The inspection of the coupling reaction between indole (1) and allyl alcohol (2 a) was chosen as a model reaction for the optimization studies (Table 1). Initially, we examined the feasibility of this transformation by using the reaction conditions previously established for the C H bond activation of indole.[13] Among a number of tested oxidants, Ag2CO3 provided the highest yield of the desired product with 21 % (Table 1, entries 1–5). Increasing the amount of the oxidant did not give the improved results (Table 1, entry 6). Gratifyingly, when N-methyl indole was chosen as the substrate for this transformation, with 1.2 equivalent of 2 a and 1.5 equivalent of Ag2CO3 conducted in 2 mL of HOAc at 80 8C in the presence of 5 mol % of PdACHTUNGRE(OAc)2, the desired oxidative alkylation product 3 a was achieved in 58 % yield (Table 1, entry 7). And the structure of 3 a was confirmed by NMR spectroscopy (for details see Supporting Information). Through screening the oxidants, we found that oxygen was the best for this transformation (Table 1, entries 7–9). More satisfying isolated yield (92 %) could be obtained by decreasing reaction temperature to room tempera-
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COMMUNICATION Table 1. Screening reaction conditions of the Pd-catalyzed oxidative alkylation of indole.[a]
Entry
Oxidant
Solvent
Catalyst
R
Yield [%][b]
1 2 3 4 5 6[c] 7 8 9 10[d] 11[e] 12[e] 13[e] 14[e] 15[e] 16[e]
CuACHTUNGRE(OAc)2 BQ Ag2CO3 1 atm O2 Ag2CO3 Ag2CO3 Ag2CO3 CuACHTUNGRE(OAc)2 1 atm O2 1 atm O2 1 atm O2 1 atm O2 1 atm O2 1 atm O2 1 atm O2 1 atm O2
DMA DMA DMA DMA CH3COOH DMA HOAc HOAc HOAc HOAc HOAc CH3CN DMSO HOAc HOAc HOAc
PdACHTUNGRE(OAc)2 PdACHTUNGRE(OAc)2 PdACHTUNGRE(OAc)2 PdACHTUNGRE(OAc)2 PdACHTUNGRE(OAc)2 PdACHTUNGRE(OAc)2 PdACHTUNGRE(OAc)2 PdACHTUNGRE(OAc)2 PdACHTUNGRE(OAc)2 PdACHTUNGRE(OAc)2 PdACHTUNGRE(OAc)2 PdACHTUNGRE(OAc)2 PdACHTUNGRE(OAc)2 – PdCl2 PdACHTUNGRE(OAc)2
R=H R=H R=H R=H R=H R=H R = Me R = Me R = Me R = Me R = Me R = Me R = Me R = Me R = Me R = Ac
13 trace 21 trace 17 12 58 29 73 86 97(92) N. R. N. R. N.R. Trace N.R.
[a] Unless otherwise noted, the reaction was carried out with 1 (0.50 mmol), 2 a (1.2 equiv), oxidant (0.75 mmol), catalyst (0.025 mmol), solvent (2 mL), 80 8C, overnight, under N2. [b] The yield was determined by GC analysis with naphthalene as the internal standard. Data in parentheses is the yield of isolated product. [c] Oxidant (1 mmol) was used. [d] 50 8C. [e] Room temperature.
ture (Table 1, entries 10 and 11). The acidic solvent was essential for this reaction (Table 1, entries 12 and 13). Control reactions demonstrated that 3 a was not formed in the absence of Pd catalyst. Additionally, electron-deficient N-Ac indole failed to give the corresponding product. With the optimal reaction conditions in hand, we next explored the generality of the reaction with other substituted indoles and allyl alcohols under the optimized conditions. Various allyl alcohols were employed to couple with 1methyl-1H-indole. It is noteworthy that the allyl secondary alcohols were converted into the corresponding b-indole ketones in high yields at higher temperature (Table 2, 3 b and c). The sole chemical selectivity can be obtained when the substrate contains more than one C C double bond (Table 2, 3 d). Subsequently, a series of substituted indoles were found to be suitable substrates for this transformation. The oxidative alkylation of 7-methyl indole with allyl alcohol proceeded at room temperature to give the corresponding product in 88 % yield (Table 2, 3 e). Different 5-substituted indoles, including some with electron-donating groups (R = Me, OMe) and some with electron-withdrawing groups (R = F, Cl, CN), were converted into the corresponding bindole ketones and aldehydes with good to excellent yields (Table 2, 3 f–k). To our delight, the C H activation occurred at the C-2 position when 3-methyl indole was used as the substrate (Table 2, 3 l). Additionally, N-benzyl substituted indole was also suitable substrate for this transformation (Table 2, 3 m). Then, we looked forward to expanding the scope to other heterocycles. To our delight, 2-substituted thiophenes were
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Table 2. Pd-catalyzed oxidative alkylation of indoles with allyl alcohols.[a]
[a] Unless otherwise noted, the reactions were carried out with 1 (0.50 mmol), 2 (1.2 equiv), oxidant (0.75 mmol), PdACHTUNGRE(OAc)2 (0.025 mmol), in HOAc (2 mL), under 1 atm of O2.
converted to the b-thiophene aldehydes and ketone with moderate to good yields (Table 3, 3 n and o). It is worth mentioning that 3 p could be obtained through Heck reaction of 2-bromothiophene with but-3-en-2-one, followed by an oxidative Heck reaction with allyl alcohol. Similarly, both electron-rich and electron-deficient 2-substituted furans could be converted to the b-furan ketones (Table 3, 3 q and r). Table 3. Pd-catalyzed oxidative alkylation of heterocycles with allyl alcohols.[a]
[a] Unless otherwise noted, the reactions were carried out with 1 (0.50 mmol), 2 (1.2 equiv), oxidant (0.75 mmol), PdACHTUNGRE(OAc)2 (0.025 mmol), in HOAc (2 mL), under 1 atm of O2.
After the successful application of heterocyclic nucleophiles for this transformation, we looked to expand the scope to aryl-nucleophiles, originating from decarboxylation
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H. Jiang et al.
of carboxylic acids. It was known that a limitation of decarboxylative coupling was that the substrates are usually limited to ortho-substituted benzoic acids.[8, 10] With the development of decarboxylative coupling, aryl phosphonic acids, aryl sulfinic acids, and arylsulfonyl hydrazides[11, 14] have been described as the source of aryl group without the ortho-substituted limitation. To further address the scope, selectivity, and productivity issues, we chose arylsulfonyl hydrazides as the coupling partners with allylic alcohols for this oxidative-coupling reaction through selective b-hydride elimination to construct b-aryl ketones. Fortunately, we found that the reaction of 4-methylbenzenesulfonohydrazide (4 a) (0.33 mmol) with 2 b (0.5 mmol) conducted in a DMSO/DMF (1:20) solvent system at 120 8C in the presence of 10 mol % of PdACHTUNGRE(OAc)2, and nBu4NBr (0.5 mmol) under 1 atm O2 gave the desired product 5 a in 84 % yield (Table 4; see Supporting Information for details). We next examined other substrates in this Pd-catalyzed oxidative Heck reaction. Under the optimized conditions, 4 a
Table 4. Pd-catalyzed oxidative coupling reactions between arylsulfonyl hydrazides 4 and allyl alcohols 2.
[a] Unless otherwise noted, the reactions were carried out with 4 (0.33 mmol), 2 (0.5 mmol), PdACHTUNGRE(OAc)2 (10 mol %), nBu4NBr (0.5 mmol), DMF/DMSO = 20:1 (3 mL), H2O (0.2 mL) under 1 atm of O2 at 120 8C for 2–12 h. [b] Without adding H2O (0.2 mL) under 1 atm of O2 at 70 8C.
coupled with a range of p-substituted 1-phenylprop-2-en-1ols in modest to good yields (Table 4). In contrast with the excellent yields of 5 g and h, the strong electron-donating groups decreased the yields of the corresponding products (Table 4, 5 b–d). These reactions were compatible with furan and C C double bond moieties (Table 4, 5 j and k). It was interesting to note that benzenesulfonohydrazide with electron-withdrawing or electron-donating groups are also suitACHTUNGREable substrates for this transformation. When alkyl-substituted allylic alcohols were used as the coupling partner, the reaction temperature can be lowered to 70 8C and without adding 0.2 mL of water (Table 4, 5 o–y). Encouraged by these promising results, we further performed the d-labelled experiments. 4-methylbenzenesulfonohydrazide was employed to couple with [D]-1-phenylprop-2en-1-ol under the standard conditions [Eq. (3)]. It was as expected that a-[D]-b-aryl ketone was the sole product without the b-D elimination product.[8, 12, 15] No [D]-labelled product could be detected when 0.2 mL D2O was added to the cross coupling between 4-methylbenzenesulfonohydrazide (4 a) and 1-phenylprop-2-en-1-ol under the standard condi-
tions [Eq. (4)]. It indicated that 5 a was not formed via the protonolysis of intermediate D by D2O.[16] On the basis of the above results, a tentative mechanism for the Pd-catalyzed oxidative coupling reaction between (hetero)arenes and allylic alcohols through selective b-H elimination to synthesize b-(hetero)aryl ketones and aldehydes was proposed (Scheme 1). When aromatic heterocycles were used as the substrates, the arylpalladium species I was formed through the PdII-catalyzed C H activation of aromatic heterocycles. In the presence of oxygen, intermediate C could be obtained through the sequent b-H elimination and loss of nitrogen from intermediate B. Similarly, the
Scheme 1. Proposed catalytic cycle.
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Aerobic Oxidative Coupling
COMMUNICATION
elimination of SO2 from complex C generated ArPdX, which was inserted by the allylic alcohols to give intermediate II. The selective b-H elimination from intermediate II generated PdII species III, which then inserted into the enol to afford the critical intermediate IV. This process realized the hydrogen transfer, just like the Wacker process.[17] The desired products could then be formed through two controversial approaches: b-H elimination from a-OH groups or the anion-mediated reductive elimination.[17a] In order to further demonstrate the generality of this type of catalytic cycle, we chose (E)-styrylboronic acid as the source of alkenyl nucleophile to couple with allylic alcohols.[7] Fortunately, we isolated the corresponding b-alkenyl ketone and aldehyde products in 73 and 58 % yields, respectively (Scheme 2).
Scheme 2. Pd-catalyzed oxidative coupling between alkenyl nucleophile and allylic alcohol.
In conclusion, we have developed a simple and efficient method for the Pd-catalyzed oxidative coupling reaction between allylic alcohols and (hetero)arenes and alkenyl nucleophiles to construct b-aryl/alkenyl ketones and aldehydes through selective b-H elimination. This work opens up a new approach to realize the selective b-H elimination in Pd-catalyzed oxidative Heck reaction of electronically nonbiased olefins. Tentative mechanistic studies indicate the hydrogen transfer might go through the Wacker oxidative process and may be a significant model to study the Wacker oxidation. Further studies into the use of unactivated arenes as the source of aryl nucleophiles, as well as detailed mechanistic investigations, are underway in our laboratory.
Experimental Section General procedure for the palladium-catalyzed Heck-type reaction of heterocycles and allylic alcohols: To a Schlenk tube were added heterocycles (0.5 mmol), allylic alcohol (0.6 mmol), PdACHTUNGRE(OAc)2 (5 mol %) and CH3COOH (2 mL) and were stirred overnight at the required reaction temperature. After the reaction was finished, the solution was quenched with aqueous NaHCO3 (10 mL) and extracted with ethyl acetate (3 10 mL). The organic extracts were concentrated in vacuum, and the resulting residue was purified by silica gel column chromatography using light petroleum ether/ethyl acetate as eluent to afford the desired product.
Acknowledgements The authors are grateful to the National Natural Science Foundation of China (20932002 and 21172076), National Basic Research Program of
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China (973 Program) (2011CB808600), the Changjiang Scholars and Innovation Team Project of Ministry of Education, Doctoral Fund of Ministry of Education of China(20090172110014) and Guangdong Natural Science Foundation (10351064101000000) for financial support.
Keywords: Heck reaction · hydrogen migration · oxidative alkylation · oxygen · palladium
[1] a) M. Oestreich, The Mizoroki – Heck reaction, Wiley, Hoboken, 2008; b) R. F. Heck, J. P. Nolley, J. Org. Chem. 1972, 37, 2320; c) T. Mizoroki, K. Mori, A. Ozaki, Bull. Chem. Soc. Jpn. 1971, 44, 581; d) R. F. Heck, Acc. Chem. Res. 1979, 12, 146; e) W. Cabri, I. CanACHTUNGREdiani, Acc. Chem. Res. 1995, 28, 2; f) A. F. Littke, G. C. Fu, J. Am. Chem. Soc. 2001, 123, 6989; g) B. P. Carrow, J. F. Hartwig, J. Am. Chem. Soc. 2010, 132, 79. [2] a) I. P. Beletskaya, A. V. Cheprakov, Chem. Rev. 2000, 100, 3009; b) K. C. Nicolaou, P. G. Bulger, D. Sarlah, Angew. Chem. 2005, 117, 4516; Angew. Chem. Int. Ed. 2005, 44, 4442. [3] a) G. D. Daves, A. Hallberg, Chem. Rev. 1989, 89, 1433; b) W. Cabri, I. Candiani, A. Bedeschi, R. Santi, J. Org. Chem. 1990, 55, 3654; c) K. S. A. Vallin, M. Larhed, A. Hallberg, J. Org. Chem. 2001, 66, 4340; d) J. Ruan, J. Xiao, Acc Chem. Res. 2011, 44, 614; e) J. Mo, J. Xiao, Angew. Chem. 2006, 118, 4258; Angew. Chem. Int. Ed. 2006, 45, 4152; f) J. Mo, L. Xu, J. Ruan, S. Liu, J. Xiao, Chem. Commun. 2006, 3591; g) R. Matsubara, A. C. Gutierrez, T. F. Jamison, J. Am. Chem. Soc. 2011, 133, 19020; h) J. Ruan, J. A. Iggo, N. G. Berry, J. Xiao, J. Am. Chem. Soc. 2010, 132, 16689. [4] a) L. Qin, X. Ren, Y. Lu, Y. Li, J. Zhou, Angew. Chem. 2012, 124, 6017; Angew. Chem. Int. Ed. 2012, 51, 5915. [5] Selective b-H elimination in oxidative Heck reactions: a) J. Le Bras, J. Muzart, Chem. Rev. 2011, 111, 1170; b) J. Le Bras, J. Muzart, Tetrahedron 2012, 68, 10065; c) Y. Su, N. Jiao, Org. Lett. 2009, 11, 2980; d) P. Hu, J. Kan, W. Su, M. Hong, Org. Lett. 2009, 11, 2341; e) C. Zhu, J. R. Falck, Org. Lett. 2011, 13, 1214; f) C. Zhu, J. R. Falck, Angew. Chem. 2011, 123, 6756; Angew. Chem. Int. Ed. 2011, 50, 6626; g) C. Zheng, D. Wang, S. S. Stahl, J. Am. Chem. Soc. 2012, 134, 16496; h) A. S. Tsai, M. Brasse, R. G. Bergman, J. A. Ellman, Org. Lett. 2011, 13, 540. [6] a) D. Pan, A. Chen, Y. Su, W. Zhou, S. Li, W. Jia, J. Xiao, Q. Liu, L. Zhang, N. Jiao, Angew. Chem. 2008, 120, 4807; Angew. Chem. Int. Ed. 2008, 47, 4729. [7] a) M. Chen, J. Wang, Z. Chai, C. You, A. Lei, Adv. Synth. Catal. 2012, 354, 341; b) M. Vellakkaran, M. M. S. Andappan, N. Kommu, Eur. J. Org. Chem. 2012, 4694. [8] L. Huang, J. Qi, X. Wu, K. Huang, H. Jiang, Org. Lett. 2013, 15, 2330. [9] Examples for Ar H bonds oxidative Heck Reactions: a) Y. Lu, D.H. Wang, K. M. Engle, J.-Q. Yu, J. Am. Chem. Soc. 2010, 132, 5916; b) A. Kubota, M. H. Emmert, M. S. Sanford, Org. Lett. 2012, 14, 1760; c) D.-H. Wang, K. M. Engle, B.-F. Shi, J.-Q. Yu, Science 2010, 327, 315; d) A. Vasseur, J. Muzart, J. L. Bras, Chem. Eur. J. 2011, 17, 12556; e) A. Vasseur, D. Harakat, J. Muzart, J. L. Bras, J. Org. Chem. 2012, 77, 5751; f) M. Miyasaka, K. Hirano, T. Satoh, M. Miura, J. Org. Chem. 2010, 75, 5421. [10] Examples for decarboxylative Heck-type reactions: a) A. G. Myers, D. Tanaka, M. R. Mannion, J. Am. Chem. Soc. 2002, 124, 11250; b) D. Tanaka, S. P. Romeril, A. G. Myers, J. Am. Chem. Soc. 2005, 127, 10323; c) S.-L. Zhang, Y. Fu, R. Shang, Q.-X. Guo, L. Liu, J. Am. Chem. Soc. 2010, 132, 638; d) Z. Fu, S. Huang, W. Su, M. Hong, Org. Lett. 2010, 12, 4992; e) W. I. Dzik, P. P. Lange, L. J. Gooßen, Chem. Sci. 2012, 3, 2671. [11] a) A. Inoue, H. Shinokubo, K. Oshima, J. Am. Chem. Soc. 2003, 125, 1484; b) G.-W. Wang, T. Miao, Chem. Eur. J. 2011, 17, 5787; c) J. G. Taylor, A. V. Moro, C. R. Correia, Eur. J. Org. Chem. 2011, 1403; d) M.-K. Zhu, J.-F. Zhao, T.-P. Lop, Org. Lett. 2011, 13, 6308; e) F.-
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X. Felpin, L. Nassar-Hardy, F. L. Callonnec, E. Fouquet, Tetrahedron 2011, 67, 2815. [12] L. Huang, Q. Wang, J. Qi, X. Wu, K. Huang, H. Jiang, Chem. Sci. 2013, 4, 2665. [13] a) S.-D. Yang, C.-L. Sun, Z. Fang, B.-J. Li, Y.-Z. Li, Z.-J. Shi, Angew. Chem. 2008, 120, 1495; Angew. Chem. Int. Ed. 2008, 47, 1473; b) E. M. Beck, N. P. Grimster, R. Hatley, M. J. Gaunt, J. Am. Chem. Soc. 2006, 128, 2528; c) N. P. Grimster, C. Gauntlett, C. R. A. Godfrey, M. J. Gaunt, Angew. Chem. 2005, 117, 3185; Angew. Chem. Int. Ed. 2005, 44, 3125; d) A. Garca-Rubia, R. G. Arrays, J. C. Carretero, Angew. Chem. 2009, 121, 6633; Angew. Chem. Int. Ed. 2009, 48, 6511; e) Z. Wang, K. Li, D. Zhao, J. Lan, J. You, Angew. Chem. 2011, 123, 5477; Angew. Chem. Int. Ed. 2011, 50, 5365; f) S. R. Kandukuri, J. A. Schiffner, M. Oestreich, Angew. Chem. 2012, 124, 1291; Angew. Chem. Int. Ed. 2012, 51, 1265; g) M. V. Leskinen, K.-T. Yip, A. Valkonen, P. M. Pihko, J. Am. Chem. Soc. 2012, 134, 5750.
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[14] a) X. Zhou, J. Luo, J. Liu, S. Peng, G.-J. Deng, Org. Lett. 2011, 13, 1432; b) X. Yu, X. Li, B. Wan, Org. Biomol. Chem. 2012, 10, 7479; c) B. Liu, J. Li, F. Song, J. You, Chem. Eur. J. 2012, 18, 10830; d) F.L. Yang, X.-T. Ma, S.-K. Tian, Chem. Eur. J. 2012, 18, 1582. [15] Y. Wen, L. Huang, H. Jiang, H. Chen, J. Org. Chem. 2012, 77, 2029. [16] Examples for quenching the C PdII bonds by protonolysis: a) L. Zhao, X. Lu, Org. Lett. 2002, 4, 3903; b) S. Lin, X. Lu, Org. Lett. 2010, 12, 2536; c) Q. Peng, H. Yan, X. Zhang, Y.-D. Wu, J. Org. Chem. 2012, 77, 7487. [17] a) J. A. Keith, J. Oxgaard, W. A. Goddard, J. Am. Chem. Soc. 2006, 128, 3132; b) C. N. Cornell, M. S. Sigman, J. Am. Chem. Soc. 2005, 127, 2796; c) B. J. Anderson, J. A. Keith, M. S. Sigman, J. Am. Chem. Soc. 2010, 132, 11872; d) T.-S. Mei, E. W. Werner, A. J. Burckle, M. S. Sigman, J. Am. Chem. Soc. 2013, 135, 6830.
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Received: July 27, 2013 Published online: October 21, 2013
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Aerobic Oxidative Coupling between Carbon Nucleophiles and Allylic Alcohols: A Strategy to Construct b-(Hetero)Aryl Ketones and Aldehydes through Hydrogen Migration Liangbin Huang, Ji Qi, Xia Wu, Wanqing Wu, and Huanfeng Jiang*[a] Since the early 1970s, the Pd-catalyzed Heck reaction has become a powerful tool to prepare substituted olefins.[1, 2] The main challenges in the intermolecular Heck reaction are controlling the regioselectivity and high selective b-H elimination when olefins without a significant electronic difference at the two olefinic sites are used as the substrates.[3] The groups of Stahl and Zhou recently reported ligand-controlled regioselectivity in the synthesis substituted olefins through Heck-type coupling of alkenes with vinylboronic acids and aryl triflates.[3f, 4] To solve the problem of selective b-H elimination, Sigman and co-workers designed palladium catalysts that were capable of distinguishing C H bonds on the basis of relative bond strength.[5] Jiao found that b-H elimination is highly chemoselectively controlled in a ligandfree system when allyl esters reacted with carbon electrophiles or carbon nucleophiles, due to chelation between O and Pd atoms.[6] Lei and Nacci achieved the highly selective arylation of allyl alcohols through redox-neutral pathway with iodobenzene or the oxidative approach with benzoboric acid, respectively. [Eq. (1)].[7] Recently, Pd-catalyzed oxidative coupling between benzoic acids and allyl alcohols leading to b-aryl ketones was reported.[8] However, some drawbacks of this method may limit its application. Firstly, the
[a] L. Huang, J. Qi, X. Wu, W. Wu, Prof. Dr. H. Jiang School of Chemistry and Chemical Engineering South China University of Technology Guangzhou 510640 (P. R. China) E-mail: [email protected] Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201302962.
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substrate scope is limited to ortho-substituted benzoic acids. Secondly, stoichiometric amounts of Ag salts were used as the oxidant. Herein, we present a palladium-catalyzed aerobic oxidative coupling of allylic alcohols with (hetero)aryl nucleophiles to construct b-(hetero)aryl ketones and aldehydes. Recently, increasing interest has been focused on PdII-catalyzed C H activation[9] and decarboxylation,[10] including its derivatives of carboxylate variants,[11] instead of Ar X (X = halide, OTf and metal; Tf = triflate) for cross-coupling reactions. They provided complementary approaches for obtaining carbon nucleophiles. On one hand, arylsulfonyl hydrazides are cheap and readily available carbon nucleophiles used for oxidative cross-coupling reactions. On the other hand, (hetero)arene derivatives are of great importance as building blocks for pharmaceuticals and bioactive compounds. Evidently, the direct utilization of allyl alcohols coupling with those carbon nucleophiles to obtain b-(hetero)ACHTUNGREaryl ketones and aldehydes by using oxygen as the sole oxidant would be a fascinating approach [Eq. (2)]. In addition, the frequently used strategies for C H bond alkylation are the hydroarylation of alkenes as well as direct alkylation with alkyl halides. The oxidative coupling between (hetero)arene and allyl alcohols provides an alternative approach for C H alkylation.[12] The inspection of the coupling reaction between indole (1) and allyl alcohol (2 a) was chosen as a model reaction for the optimization studies (Table 1). Initially, we examined the feasibility of this transformation by using the reaction conditions previously established for the C H bond activation of indole.[13] Among a number of tested oxidants, Ag2CO3 provided the highest yield of the desired product with 21 % (Table 1, entries 1–5). Increasing the amount of the oxidant did not give the improved results (Table 1, entry 6). Gratifyingly, when N-methyl indole was chosen as the substrate for this transformation, with 1.2 equivalent of 2 a and 1.5 equivalent of Ag2CO3 conducted in 2 mL of HOAc at 80 8C in the presence of 5 mol % of PdACHTUNGRE(OAc)2, the desired oxidative alkylation product 3 a was achieved in 58 % yield (Table 1, entry 7). And the structure of 3 a was confirmed by NMR spectroscopy (for details see Supporting Information). Through screening the oxidants, we found that oxygen was the best for this transformation (Table 1, entries 7–9). More satisfying isolated yield (92 %) could be obtained by decreasing reaction temperature to room tempera-
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COMMUNICATION Table 1. Screening reaction conditions of the Pd-catalyzed oxidative alkylation of indole.[a]
Entry
Oxidant
Solvent
Catalyst
R
Yield [%][b]
1 2 3 4 5 6[c] 7 8 9 10[d] 11[e] 12[e] 13[e] 14[e] 15[e] 16[e]
CuACHTUNGRE(OAc)2 BQ Ag2CO3 1 atm O2 Ag2CO3 Ag2CO3 Ag2CO3 CuACHTUNGRE(OAc)2 1 atm O2 1 atm O2 1 atm O2 1 atm O2 1 atm O2 1 atm O2 1 atm O2 1 atm O2
DMA DMA DMA DMA CH3COOH DMA HOAc HOAc HOAc HOAc HOAc CH3CN DMSO HOAc HOAc HOAc
PdACHTUNGRE(OAc)2 PdACHTUNGRE(OAc)2 PdACHTUNGRE(OAc)2 PdACHTUNGRE(OAc)2 PdACHTUNGRE(OAc)2 PdACHTUNGRE(OAc)2 PdACHTUNGRE(OAc)2 PdACHTUNGRE(OAc)2 PdACHTUNGRE(OAc)2 PdACHTUNGRE(OAc)2 PdACHTUNGRE(OAc)2 PdACHTUNGRE(OAc)2 PdACHTUNGRE(OAc)2 – PdCl2 PdACHTUNGRE(OAc)2
R=H R=H R=H R=H R=H R=H R = Me R = Me R = Me R = Me R = Me R = Me R = Me R = Me R = Me R = Ac
13 trace 21 trace 17 12 58 29 73 86 97(92) N. R. N. R. N.R. Trace N.R.
[a] Unless otherwise noted, the reaction was carried out with 1 (0.50 mmol), 2 a (1.2 equiv), oxidant (0.75 mmol), catalyst (0.025 mmol), solvent (2 mL), 80 8C, overnight, under N2. [b] The yield was determined by GC analysis with naphthalene as the internal standard. Data in parentheses is the yield of isolated product. [c] Oxidant (1 mmol) was used. [d] 50 8C. [e] Room temperature.
ture (Table 1, entries 10 and 11). The acidic solvent was essential for this reaction (Table 1, entries 12 and 13). Control reactions demonstrated that 3 a was not formed in the absence of Pd catalyst. Additionally, electron-deficient N-Ac indole failed to give the corresponding product. With the optimal reaction conditions in hand, we next explored the generality of the reaction with other substituted indoles and allyl alcohols under the optimized conditions. Various allyl alcohols were employed to couple with 1methyl-1H-indole. It is noteworthy that the allyl secondary alcohols were converted into the corresponding b-indole ketones in high yields at higher temperature (Table 2, 3 b and c). The sole chemical selectivity can be obtained when the substrate contains more than one C C double bond (Table 2, 3 d). Subsequently, a series of substituted indoles were found to be suitable substrates for this transformation. The oxidative alkylation of 7-methyl indole with allyl alcohol proceeded at room temperature to give the corresponding product in 88 % yield (Table 2, 3 e). Different 5-substituted indoles, including some with electron-donating groups (R = Me, OMe) and some with electron-withdrawing groups (R = F, Cl, CN), were converted into the corresponding bindole ketones and aldehydes with good to excellent yields (Table 2, 3 f–k). To our delight, the C H activation occurred at the C-2 position when 3-methyl indole was used as the substrate (Table 2, 3 l). Additionally, N-benzyl substituted indole was also suitable substrate for this transformation (Table 2, 3 m). Then, we looked forward to expanding the scope to other heterocycles. To our delight, 2-substituted thiophenes were
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Table 2. Pd-catalyzed oxidative alkylation of indoles with allyl alcohols.[a]
[a] Unless otherwise noted, the reactions were carried out with 1 (0.50 mmol), 2 (1.2 equiv), oxidant (0.75 mmol), PdACHTUNGRE(OAc)2 (0.025 mmol), in HOAc (2 mL), under 1 atm of O2.
converted to the b-thiophene aldehydes and ketone with moderate to good yields (Table 3, 3 n and o). It is worth mentioning that 3 p could be obtained through Heck reaction of 2-bromothiophene with but-3-en-2-one, followed by an oxidative Heck reaction with allyl alcohol. Similarly, both electron-rich and electron-deficient 2-substituted furans could be converted to the b-furan ketones (Table 3, 3 q and r). Table 3. Pd-catalyzed oxidative alkylation of heterocycles with allyl alcohols.[a]
[a] Unless otherwise noted, the reactions were carried out with 1 (0.50 mmol), 2 (1.2 equiv), oxidant (0.75 mmol), PdACHTUNGRE(OAc)2 (0.025 mmol), in HOAc (2 mL), under 1 atm of O2.
After the successful application of heterocyclic nucleophiles for this transformation, we looked to expand the scope to aryl-nucleophiles, originating from decarboxylation
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of carboxylic acids. It was known that a limitation of decarboxylative coupling was that the substrates are usually limited to ortho-substituted benzoic acids.[8, 10] With the development of decarboxylative coupling, aryl phosphonic acids, aryl sulfinic acids, and arylsulfonyl hydrazides[11, 14] have been described as the source of aryl group without the ortho-substituted limitation. To further address the scope, selectivity, and productivity issues, we chose arylsulfonyl hydrazides as the coupling partners with allylic alcohols for this oxidative-coupling reaction through selective b-hydride elimination to construct b-aryl ketones. Fortunately, we found that the reaction of 4-methylbenzenesulfonohydrazide (4 a) (0.33 mmol) with 2 b (0.5 mmol) conducted in a DMSO/DMF (1:20) solvent system at 120 8C in the presence of 10 mol % of PdACHTUNGRE(OAc)2, and nBu4NBr (0.5 mmol) under 1 atm O2 gave the desired product 5 a in 84 % yield (Table 4; see Supporting Information for details). We next examined other substrates in this Pd-catalyzed oxidative Heck reaction. Under the optimized conditions, 4 a
Table 4. Pd-catalyzed oxidative coupling reactions between arylsulfonyl hydrazides 4 and allyl alcohols 2.
[a] Unless otherwise noted, the reactions were carried out with 4 (0.33 mmol), 2 (0.5 mmol), PdACHTUNGRE(OAc)2 (10 mol %), nBu4NBr (0.5 mmol), DMF/DMSO = 20:1 (3 mL), H2O (0.2 mL) under 1 atm of O2 at 120 8C for 2–12 h. [b] Without adding H2O (0.2 mL) under 1 atm of O2 at 70 8C.
coupled with a range of p-substituted 1-phenylprop-2-en-1ols in modest to good yields (Table 4). In contrast with the excellent yields of 5 g and h, the strong electron-donating groups decreased the yields of the corresponding products (Table 4, 5 b–d). These reactions were compatible with furan and C C double bond moieties (Table 4, 5 j and k). It was interesting to note that benzenesulfonohydrazide with electron-withdrawing or electron-donating groups are also suitACHTUNGREable substrates for this transformation. When alkyl-substituted allylic alcohols were used as the coupling partner, the reaction temperature can be lowered to 70 8C and without adding 0.2 mL of water (Table 4, 5 o–y). Encouraged by these promising results, we further performed the d-labelled experiments. 4-methylbenzenesulfonohydrazide was employed to couple with [D]-1-phenylprop-2en-1-ol under the standard conditions [Eq. (3)]. It was as expected that a-[D]-b-aryl ketone was the sole product without the b-D elimination product.[8, 12, 15] No [D]-labelled product could be detected when 0.2 mL D2O was added to the cross coupling between 4-methylbenzenesulfonohydrazide (4 a) and 1-phenylprop-2-en-1-ol under the standard condi-
tions [Eq. (4)]. It indicated that 5 a was not formed via the protonolysis of intermediate D by D2O.[16] On the basis of the above results, a tentative mechanism for the Pd-catalyzed oxidative coupling reaction between (hetero)arenes and allylic alcohols through selective b-H elimination to synthesize b-(hetero)aryl ketones and aldehydes was proposed (Scheme 1). When aromatic heterocycles were used as the substrates, the arylpalladium species I was formed through the PdII-catalyzed C H activation of aromatic heterocycles. In the presence of oxygen, intermediate C could be obtained through the sequent b-H elimination and loss of nitrogen from intermediate B. Similarly, the
Scheme 1. Proposed catalytic cycle.
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Aerobic Oxidative Coupling
COMMUNICATION
elimination of SO2 from complex C generated ArPdX, which was inserted by the allylic alcohols to give intermediate II. The selective b-H elimination from intermediate II generated PdII species III, which then inserted into the enol to afford the critical intermediate IV. This process realized the hydrogen transfer, just like the Wacker process.[17] The desired products could then be formed through two controversial approaches: b-H elimination from a-OH groups or the anion-mediated reductive elimination.[17a] In order to further demonstrate the generality of this type of catalytic cycle, we chose (E)-styrylboronic acid as the source of alkenyl nucleophile to couple with allylic alcohols.[7] Fortunately, we isolated the corresponding b-alkenyl ketone and aldehyde products in 73 and 58 % yields, respectively (Scheme 2).
Scheme 2. Pd-catalyzed oxidative coupling between alkenyl nucleophile and allylic alcohol.
In conclusion, we have developed a simple and efficient method for the Pd-catalyzed oxidative coupling reaction between allylic alcohols and (hetero)arenes and alkenyl nucleophiles to construct b-aryl/alkenyl ketones and aldehydes through selective b-H elimination. This work opens up a new approach to realize the selective b-H elimination in Pd-catalyzed oxidative Heck reaction of electronically nonbiased olefins. Tentative mechanistic studies indicate the hydrogen transfer might go through the Wacker oxidative process and may be a significant model to study the Wacker oxidation. Further studies into the use of unactivated arenes as the source of aryl nucleophiles, as well as detailed mechanistic investigations, are underway in our laboratory.
Experimental Section General procedure for the palladium-catalyzed Heck-type reaction of heterocycles and allylic alcohols: To a Schlenk tube were added heterocycles (0.5 mmol), allylic alcohol (0.6 mmol), PdACHTUNGRE(OAc)2 (5 mol %) and CH3COOH (2 mL) and were stirred overnight at the required reaction temperature. After the reaction was finished, the solution was quenched with aqueous NaHCO3 (10 mL) and extracted with ethyl acetate (3 10 mL). The organic extracts were concentrated in vacuum, and the resulting residue was purified by silica gel column chromatography using light petroleum ether/ethyl acetate as eluent to afford the desired product.
Acknowledgements The authors are grateful to the National Natural Science Foundation of China (20932002 and 21172076), National Basic Research Program of
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China (973 Program) (2011CB808600), the Changjiang Scholars and Innovation Team Project of Ministry of Education, Doctoral Fund of Ministry of Education of China(20090172110014) and Guangdong Natural Science Foundation (10351064101000000) for financial support.
Keywords: Heck reaction · hydrogen migration · oxidative alkylation · oxygen · palladium
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Received: July 27, 2013 Published online: October 21, 2013
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