DOI: 10.1002/asia.201500236
Communication
Cascade Reactions
Platinum-Catalyzed Cascade Rearrangement Reaction of 1,5Diynyl Esters: Unusual Regioselective 1,5-Hydride Migration Hui Zhu,[a] Jiapian Huang,[a] Congbin Fan,[b] and Zhiyuan Chen*[a] Abstract: A highly regioselective sequential 1,3-acyloxy migration/pentannulation/1,5-hydride migration reaction is disclosed which provides an efficient access to (E)-2vinyl-3-oxo-1-methyleneindenes under neutral and mild reaction conditions. The migrated hydrogen atom was derived from an unactivated alkyl group, and the long-range 1,5-H shift was confirmed through related deuterium experiments.
Indenes, including 1-methyleneindenes or benzofulvenes, are an important class of conjugated carbocyclic compounds that can be found in a myriad of natural products and drugs.[1] Furthermore, indene derivatives have being widely developed as building blocks in the preparation of pharmaceutical molecules,[2] metallocene catalysts or fullerenes,[3] and as monomers for rapid polymerization reactions to afford polymer materials.[4] Therefore, it is not surprising that a general and flexible protocol to generate indene derivatives is highly desirable.[5] Besides heat- or light-induced radical cyclization of enyne-allenes,[6] transition-metal-catalyzed indene synthesis has been employed frequently in this regard, such as in the Rh- or Pdcatalyzed C¢H functionalization reaction of ketones with alkynes,[7, 8] in the Pd-catalyzed tandem cyclization of 2-alkenylphenylacetylenes with boronic acids or alcohols,[5b, 9] and in the proton-promoted intramolecular cyclization of ortho-vinyl acetophenone imines to benzofulvene derivatives.[10] The Au-catalyzed cycloisomerization of enyne systems to give 1-methyleneindenes is particularly impressive because of its perfect atom efficiency and chemical selectivity.[11] While these methods have disclosed many excellent strategies with regard to indenes or 1-methyleneindenes, less attention has been paid on reactions that focus on the generation [a] H. Zhu, J. Huang, Dr. Z. Chen Key Laboratory of Functional Small Organic Molecules Ministry of Education College of Chemistry&Chemical Engineering Jiangxi Normal University Ziyang Road 99, Nanchang, Jiangxi 330022 (P. R. China) E-mail: [email protected] [b] Dr. C. Fan Jiangxi Key Laboratory of Organic Chemistry Jiangxi Science and Technology Normal University Nanchang, Jiangxi 330013 (P. R. China). Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/asia.201500236. Chem. Asian J. 2015, 10, 1463 – 1466
of 2-vinyl-3-oxo-1-methyleneindenes, and only few examples have been reported that employed photochemical Myers–Saito bi-radical cyclizations to give 2-vinyl-1-methyleneindenes.[6, 12] Given the potential value of 1-methyleneindene derivatives to be widely used in medicinal and materials sciences, or to serve as versatile building blocks in organic synthesis, we reasoned that the structurally interesting 2-vinyl-3-oxo-1-methyleneindenes would be useful for subsequent biological evaluations or for the elaboration of other highly fused cyclic derivatives. Most recently, we have reported a regioselective Pt-catalyzed cycloisomerization reaction of benzoendiynyl esters to afford benzofulvene diketone derivatives.[13] Based on a mechanistic study, the reaction is believed to proceed via a platinumcatalyzed intramolecular 1,3-acyloxy migration, 5-exo-dig cyclization, and a long-range 1,5-acyl migration reaction. Based on this assumption, we envisioned that a novel unconventional 2vinyl-3-oxo-1-methyleneindene ester synthesis could be realized by allowing the plausible reactive metalla-substituted species to react with an active electrophile.[14] We envisioned that application of this migratory protocol to 2-methyl-4-(2-(phenylethynyl)phenyl)but-3-yn-2-yl acetate 1 a under suitable catalytic conditions might first lead to carboxyallene complexes A through a [3.3]-acyloxy migration, and subsequent 5-exo-dig cyclization may form five-membered metalla-containing species B. Next, the alkyl C¢H bond which was attached at the 2-vinylindene position could be selectively activated under the direction of the 3-oxonium carbonyl group, thus facilitating the final long-range 1,5-protodemetallation reaction to give 2-vinyl-3-oxo-1-methyleneindenes acetate 2 a, and simultaneously regenerate the metal catalyst (Scheme 1). Alternatively, the 3-oxonium carbonyl moiety in B might undergo hydrolysis and C-M protonation to give 2-vinyl3-oxo-1-methyleneindenone 2 a’. Although this protocol might seem workable, the following two challenges could exist: (1) The structurally bulky alkyl group might hamper the 5-exodig cyclization process of metalla-complex A and (2) the hydrogen atom might not migrate from the chemically inert alkyl group, thus terminating the whole catalytic transformation. Stimulated by the aforementioned highly interesting targets, we set out to explore this chemistry in detail. We anticipated that our approach would be an excellent surrogate for the preparation of the synthetically versatile 1-methyleneindene aromatic compounds. After extensive survey of the conditions, we found that the cyclization reaction of compound 1 a using 5.0 mol % of PtCl2 in 0.1 m of p-xylene at 60 8C for 12 h provided compound (E)-1-benzylidene-2-(prop-1-en-2-yl)-1H-inden-3-yl
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Communication
Scheme 1. Proposed synthetic route for the generation of (E)-2-vinyl-3-oxo1-methyleneindene.
acetate 2 a in 83 % yield under synthetically neutral conditions (Table 1, entry 1).[15] The (E)-configuration of compound 2 a was further supported by 1H-1H COSY and HMQC experiments. This result suggest that the syn-nucleophilic attack of the carboxyallene to the platinum-activated triple bond in complex A should favor the subsequent 5-exo-dig cyclization reaction, thus forming the exocyclic double bond structure of Pt-containing intermediate B.[16] Surprisingly, compound 2 a’ was not observed when 1 a was used as the starting material in our testing reactions. Ag + and Au3 + salts worked also in this reaction, albeit with moderate efficiency (Table 1, entries 2–5). Note that an Table 1. Screening of the reaction conditions.[a]
Entry
Variation of the reaction conditions
Yield [%][a]
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19
Standard conditions AgBF4 (5 mol %) instead of PtCl2 AgOTf (5 mol %) instead of PtCl2 Ph3PAuCl (5 mol %) instead of PtCl2 AuCl3 (5 mol %) instead of PtCl2 Pt(COD)Cl2 (5 mol %) instead of PtCl2 Pt(acac)2 (5 mol %) instead of PtCl2 Pt(PhCN)2Cl2(5 mol %) instead of PtCl2 Under CO (1 atm) atmosphere Under O2 (1 atm) atmosphere H2O (1.0 eq) as additive MeOH (1.0 eq) as additive Toluene (0.1 M) instead of p-xylene THF (0.1 M) instead of p-xylene DCE (0.1 M) instead of p-xylene MeCN (0.1 M) instead of p-xylene DMF (0.1 M) instead of p-xylene PtCl2 (2.5 mol %) p-xylene (0.067 M)
83 31 56 trace 49 trace trace 75 52 69 71 77 72 55 30 n.r. trace 73[b] 36[b]
[a] Reaction conditions: compound 1 a (0.3 mmol), PtCl2 (0.015 mmol), pxylene (3.0 mL), 60 8C, 10–12 h, isolated yield of 2 a. [b] Reaction time = 18 h. DCE = 1,2-dichloroethane; Tf = trifluoromethylsulfonate. Chem. Asian J. 2015, 10, 1463 – 1466
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AuI-complex performed rather sluggish in the current cyclization reaction (Table 1, entry 4).[17] Since a platinum catalyst constantly showed a good reactivity in this type of 1,3-acyloxy/1,5H migration reaction,[13a] we next switched our attention to different types of Pt catalysts. While organometallic complexes such as Pt(COD)Cl2 and Pt(acac)2 were inert for this reaction, a good conversion was observed when Pt(PhCN)2Cl2 was used, and PtCl2 proved to be the optimal catalyst (Table 1, entries 1 and 6–8). A metal-free experiment revealed that no conversion occurred in the reaction, and other PtIV catalysts, including PtPh4 and PtCl4, did not work at all (data not shown). Using carbon monoxide (CO) or dioxygen (O2) did not improve the chemical yield of 2 a (Table 1, entries 9 and 10). Interestingly, unlike our previous Pt-catalyzed 1,5-acyl migration reaction, which was very sensitive to moisture, water did not affect the current transformation;[13a] the product 2 a could be isolated in 71 % or 77 % yield when 1.0 equivalent of proton solvent was added into the reaction system (Table 1, entries 11–12). With respect to the solvent effect, conventional polar solvents such as 1,2-dichloroethane (DCE), MeCN, and DMF were less conducive, presumably due to competitive side reactions (Table 1, entries 13–17). While lowering of the catalyst loading to 2.5 mol % resulted in a prolonged reaction time and a reduced yield of 73 %, diluting the reaction concentration in p-xylene to 0.067 m had a much worse impact on the chemical efficiency (Table 1, entries 18–19). With the optimal conditions as shown (Table 1, entry 1) in hand, the scope of this reaction was then investigated (Table 2). The migratory ability of the acyl moiety (R3CO) in compound 1 (R1 = Me, and R2 = H) was first examined. With the acyl group of 1 a replaced by a propionyl or a cyclohexanecarbonyl group, the reaction proceeded smoothly to afford the desired 2-vinyl-3-oxobenzofulvenes 2 b and 2 c in 63 % and 61 % yield, respectively. Good yields were obtained when aromatic migratory groups (R3) were attached at the carbonyl position. For example, the ester group of R3 with electron-donating (2 e) or weakly electron-withdrawing (2 f–2 i) substituents or no substitution (2 d and 2 j) underwent the reaction smoothly, affording the corresponding products in 66 % to 84 % yields. The structure of compound 2 f was identified unambiguously by X-ray diffraction analysis.[18] In the case of a,b-unsaturated alkenes, while compound 2 k was produced in only 57 % yield using methacryloyl as the migratory acyl group, the reaction proceeded nicely with cinnamoyl (2 l). A heterocyclic furyl group could also be tolerated in this reaction, and the structurally divergent compound 2 m was obtained in 71 % yield. A moderate yield of 47 % could be obtained when the structurally rigid cyclohexyl group was located at the propargyl moiety (2 m), which could be possibly rationalized as a less ratable cyclohexyl loop as compared with the free methyl group. A complex mixture was observed when one methyl group (R1 = R2 = H) was located at the propargyl position of 1 n. On the other hand, the results showed that a chemoselective reaction was observed when methyl and ethyl groups were simultaneously present in the propargyl position of 1 o (R1 = R2 = Me); the dehydrogenative process selectively occurred at the methyl group, and the corresponding
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Communication Table 2. Scope of the 2-vinyl-3-oxo-1-methyleneindenes catalyzed by PtCl2.[a,b]
Table 3. Scope of the substituents in substrates 1.
[a] Reaction conditions: compound 1 (0.3 mmol), PtCl2 (0.015 mmol), pxylene (3.0 mL), 60 8C, 12 h. [b] For 24 h. [c] At 90 8C for 24 h. [d] With H2O (1.0 equiv).
[a] Reaction conditions: compound 1 (0.3 mmol), PtCl2 (0.015 mmol), pxylene (3.0 mL), 60 8C, 10–12 h. Isolated yield. [b] At 60 8C for 12 h, then 80 8C for 6 h. [c] With PtCl2 (10 mol %), 80 8C, 24 h. [d] For 24 h.
product 2 o was isolated in 60 % yield. It is interesting to note that the dehydrogenation selectively occurred at the CH3 group rather than at the CH2CH3 group, since the C¢H bond energy of Me is relatively higher than that of Et. Therefore, this result seems to suggest that the steric effect dominates over the electronic effect in the current long-range 1,5-hydride migration process. We have also tried the substrate 1 p, which possesses a cationic-stabilizing benzyl group at the propargyl position (R1 = Et, R2 = OBn); however, the reaction was very complex, and the starting material 1 p decomposed rapidly under the standard conditions.[19] The effect of the electronic variation in the R4 and R5 position of compound 1 were next examined under the optimized conditions. The reaction displayed excellent functional group compatibility in terms of the substituents which were attached on the aromatic ring or on the alkyl group of 1 (Table 3). For example, the additional hydrogen atom (R4) in the central aromatic ring of compound 1 can be readily displaced by electron-donating groups (MeO or Me) or strong electron-withdrawing groups (CF3O or F), affording the expected 2-vinyl-3Chem. Asian J. 2015, 10, 1463 – 1466
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oxo-1-methyleneindenes (3 a–3 d) in moderate to good yields. The fluoro- and trifluoromethoxyl-substituted benzofulvenes (3 c, 3 d) are particularly noteworthy, as it is well known that fluorinated 1-methyleneindenes usually exhibit interesting physicochemical and biological properties.[13b] Various substitutions, such as methoxy (3 e), methyl (3 f), fluoride (3 g), chloride (3 h), ester (3 i), nitro (3 j), and nitrile (3 k), were introduced into the phenyl group at the R5 position to probe the reactivity and regioselectivity. A five-membered heterocyclic thiophenyl group can be well tolerated in the reaction, and the desired product (3 l) can be isolated in reasonable yield. Even though many aryl groups were readily tolerated, the reaction was apparently sensitive to a steric effect because 3 m, which contains a bulky tert-butyl group, was not obtained. This result indicated that steric congestion has a strong influence on the formation of intermediate B from its precursor species A (Scheme 1). Interestingly, the silyl group could be successfully incorporated; the trimethylsilyl (TMS)-substituted compound 3 n was generated in 68 % yield under the standard conditions. The yield of 3 n could be improved to 74 % when 1.0 equivalent of water was added into the reaction system. To gain insight into the reaction mechanism, the deuterium labeled compound 1 n-d6 was synthesized using [D6]acetone as a building block [Scheme 2, Eq. (1)]. The reaction was highly regioselective since 3 n-d6 was successfully isolated without deuterium loss under the standard conditions. This result demonstrated that the migrated hydrogen atom was derived from the unactivated methyl group and that a regioselective longrange 1,5-H shift process was involved in the key intermediate B (Scheme 1). Furthermore, to clarify the possibility whether the reactive C-Pt bond in species B was protonized by a trace amount of water, we have carried out the cyclization reaction of compound 1 n in the presence of 1.0 equivalent of D2O; the
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Communication Keywords: 1,5-diynyl esters · 1,5-hydride migration · platinum catalysis · rearrangements · regioselective
Scheme 2. Evidence of the regioselective long-range 1,5-hydride migration.
product 3 n was isolated and no deuterium incorporation was detected [Scheme 2, Eq. (2)]. These results revealed that the 1,5-H migration was an intramolecular process and no deuterium scrambling occurred during the process. In conclusion, we have developed an efficient and regioselective synthesis of (E)-2-vinyl-3-oxo-1-methyleneindenes through a platinum-catalyzed sequential 1,3-acyloxy migration/ pentannulation/long-range 1,5-hydride migration reaction under neutral and mild conditions. The deuterium labeling experiments clearly established the reaction pathway via the key intermediate B and an intramolecular long-range 1,5-proto-deplatinalation process. We therefore expect that this unusual 1,5-H migration mode opens up new opportunities in the search for unactivated alkyl C¢H activation reactions. Further studies on the application of this novel synthetic protocol can be envisioned and are being explored in the group.
Experimental Section Standard procedure for the synthesis of 2-vinyl-3-oxo-1methyleneindenes 2 a. A 25 mL Schlenk tube equipped with a Teflon-coated magnetic stir bar was charged with PtCl2 (5 mol %, 0.03 mmol), compound 1 a (0.3 mmol, 1.0 equiv), and 3.0 mL of anhydrous p-xylene. The reaction was stirred at 60 8C for 12 h. After completion of the reaction as indicated by TLC, the mixture was cooled to room temperature, diluted with ethyl acetate, and extracted with water. The organic phase was collected and washed with saturated NaCl (aq.), dried over anhydrous Na2SO4, and concentrated. The residue was purified by column chromatography on silica gel (petroleum ether/ ethyl acetate, 200:1) to give the corresponding pure product 2 a.
Acknowledgements We thank the National Natural Science Foundation of China (21462022, 21363009), the NSF of Jiangxi Province (20133ACB20008, 20142BAB203005) for financial support. Chem. Asian J. 2015, 10, 1463 – 1466
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[1] For a rencent review: G. Qiu, J. Wu, Synlett 2014, 25, 2703, and the references therein. [2] a) J. Vicente, J. Abad, J. Gil-Rubio, Organometallics 1995, 14, 2677; b) K. Alexander, L. Julien, B. Carsten, Synlett 2004, 2397. [3] a) S. Lin, R. Waymouth, Acc. Chem. Res. 2002, 35, 765; b) H. G. Alt, A. Kçppl, Chem. Rev. 2000, 100, 1205; c) L. Scott, M. Boorum, B. McMahon, S. Hagen, J. Mack, J. Blank, H. Wegner, A. Meijere, Science 2002, 295, 1500; d) M. Boorum, Y. VasilÀv, T. Drewello, L. Scott, Science 2001, 294, 828. [4] A. Cappelli, S. Galeazzi, G. Giuliani, M. Anzini, A. Donati, L. Zetta, R. Mendichi, M. Aggravi, G. Giorgi, E. Paccagnini, S. Vomero, Macromolecules 2007, 40, 3005. [5] For examples, see: a) D. Campolo, T. Arif, C. Borie, D. Mouysset, N. Vanthuyne, J. Naubron, M. Bertrand, M. Nechab, Angew. Chem. Int. Ed. 2014, 53, 3227; Angew. Chem. 2014, 126, 3291; b) S. Ye, J. Wu, Org. Lett. 2011, 13, 5980; c) P. Cordier, C. Aubert, M. Malacria, E. Lacúte, V. Gandon, Angew. Chem. Int. Ed. 2009, 48, 8757; Angew. Chem. 2009, 121, 8913. Radical cyclization: d) S. Kovalenko, S. Peabody, M. Manoharan, R. Clark, I. Alabugin, Org. Lett. 2004, 6, 2457. [6] a) M. Schmittel, C. Vavilala, J. Org. Chem. 2005, 70, 4865; b) G. Bucher, A. Mahajan, M. Schmittel, J. Org. Chem. 2008, 73, 8815. [7] F. W. Patureau, T. Besset, N. Kuhl, F. Glorius, J. Am. Chem. Soc. 2011, 133, 2154. [8] J. Hwang, Y. H. Jung, Y. Hong, S. Jeon, I. Jeong, J. Fluorine Chem. 2011, 132, 1227. [9] a) S. Ye, K. Gao, H. Zhou, X. Yang, J. Wu, Chem. Commun. 2009, 5406; b) S. Ye, H. Ren, J. Wu, J. Comb. Chem. 2010, 12, 670. [10] P. Lee, T. Fujita, N. Yoshikai, J. Am. Chem. Soc. 2011, 133, 17283. [11] a) L. Ye, Y. Wang, D. Aue, L. Zhang, J. Am. Chem. Soc. 2012, 134, 31; b) A. S. K. Hashmi, I. Braun, P. Nosel, J. Schadlich, M. Wieteck, M. Rominger, Angew. Chem. Int. Ed. 2012, 51, 4456; Angew. Chem. 2012, 124, 4532. [12] Myers–Saito cyclization: a) A. G. Myers, E. Y. Kuo, N. S. Finney, J. Am. Chem. Soc. 1989, 111, 8057; b) R. Nagata, H. Yamanaka, E. Okazaki, I. Saito, Tetrahedron Lett. 1989, 30, 4995. [13] a) Z. Chen, X. Jia, J. Huang, J. Yuan, J. Org. Chem. 2014, 79, 10674; b) Q. Xiao, H. Zhu, G. Li, Z. Chen, Adv. Synth. Catal. 2014, 356, 3809; c) Z. Chen, X. Jia, C. Ye, G. Qiu, J. Wu, Chem. Asian J. 2014, 9, 126; d) Z. Chen, M. Zeng, J. Yuan, Q. Yang, Y. Peng, Org. Lett. 2012, 14, 3588. [14] For a recent review: H. Zhu, B. Yan, Y. Cao, Z. Chen, Chin. J. Org. Chem. 2015, 35, 509. [15] For a Pt-catalyzed 3.3-acyloxy migration reaction, see: G. Zhang, V. Catalano, L. Zhang, J. Am. Chem. Soc. 2007, 129, 11358. [16] For theoretical studies on the Pt-catalyzed cycloisomerization of 1,6enynes, see: a) S. Baugmarten, D. Lesage, V. Gandon, J. Goddard, M. Malacria, J. Tabet, Y. Gimbert, L. Fensterbank, ChemCatChem 2009, 1, 138; b) Y. Gimbert, L. Fensterbank, V. Gandon, J. Goddard, D. Lesage, Organometallics 2013, 32, 374. [17] For Au-catalyzed [3.3]-acyloxy migrations, see: a) Y. Chen, M. Chen, Y. Liu, Angew. Chem. Int. Ed. 2012, 51, 6493; Angew. Chem. 2012, 124, 6599; b) D. Lebœuf, A. Simonneau, C. Aubert, M. Malacria, V. Gandon, L. Fensterbank, Angew. Chem. Int. Ed. 2011, 50, 6868; Angew. Chem. 2011, 123, 7000; c) J. Zhao, C. O. Hughes, F. D. Toste, J. Am. Chem. Soc. 2006, 128, 7436. [18] CCDC 1040967 (2 f) contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_ request/cif. [19] B. Bolte, Y. Odabachian, F. Gagosz, J. Am. Chem. Soc. 2010, 132, 7294. Manuscript received: March 12, 2015 Accepted article published: April 30, 2015 Final article published: May 27, 2015
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Cascade Reactions
Platinum-Catalyzed Cascade Rearrangement Reaction of 1,5Diynyl Esters: Unusual Regioselective 1,5-Hydride Migration Hui Zhu,[a] Jiapian Huang,[a] Congbin Fan,[b] and Zhiyuan Chen*[a] Abstract: A highly regioselective sequential 1,3-acyloxy migration/pentannulation/1,5-hydride migration reaction is disclosed which provides an efficient access to (E)-2vinyl-3-oxo-1-methyleneindenes under neutral and mild reaction conditions. The migrated hydrogen atom was derived from an unactivated alkyl group, and the long-range 1,5-H shift was confirmed through related deuterium experiments.
Indenes, including 1-methyleneindenes or benzofulvenes, are an important class of conjugated carbocyclic compounds that can be found in a myriad of natural products and drugs.[1] Furthermore, indene derivatives have being widely developed as building blocks in the preparation of pharmaceutical molecules,[2] metallocene catalysts or fullerenes,[3] and as monomers for rapid polymerization reactions to afford polymer materials.[4] Therefore, it is not surprising that a general and flexible protocol to generate indene derivatives is highly desirable.[5] Besides heat- or light-induced radical cyclization of enyne-allenes,[6] transition-metal-catalyzed indene synthesis has been employed frequently in this regard, such as in the Rh- or Pdcatalyzed C¢H functionalization reaction of ketones with alkynes,[7, 8] in the Pd-catalyzed tandem cyclization of 2-alkenylphenylacetylenes with boronic acids or alcohols,[5b, 9] and in the proton-promoted intramolecular cyclization of ortho-vinyl acetophenone imines to benzofulvene derivatives.[10] The Au-catalyzed cycloisomerization of enyne systems to give 1-methyleneindenes is particularly impressive because of its perfect atom efficiency and chemical selectivity.[11] While these methods have disclosed many excellent strategies with regard to indenes or 1-methyleneindenes, less attention has been paid on reactions that focus on the generation [a] H. Zhu, J. Huang, Dr. Z. Chen Key Laboratory of Functional Small Organic Molecules Ministry of Education College of Chemistry&Chemical Engineering Jiangxi Normal University Ziyang Road 99, Nanchang, Jiangxi 330022 (P. R. China) E-mail: [email protected] [b] Dr. C. Fan Jiangxi Key Laboratory of Organic Chemistry Jiangxi Science and Technology Normal University Nanchang, Jiangxi 330013 (P. R. China). Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/asia.201500236. Chem. Asian J. 2015, 10, 1463 – 1466
of 2-vinyl-3-oxo-1-methyleneindenes, and only few examples have been reported that employed photochemical Myers–Saito bi-radical cyclizations to give 2-vinyl-1-methyleneindenes.[6, 12] Given the potential value of 1-methyleneindene derivatives to be widely used in medicinal and materials sciences, or to serve as versatile building blocks in organic synthesis, we reasoned that the structurally interesting 2-vinyl-3-oxo-1-methyleneindenes would be useful for subsequent biological evaluations or for the elaboration of other highly fused cyclic derivatives. Most recently, we have reported a regioselective Pt-catalyzed cycloisomerization reaction of benzoendiynyl esters to afford benzofulvene diketone derivatives.[13] Based on a mechanistic study, the reaction is believed to proceed via a platinumcatalyzed intramolecular 1,3-acyloxy migration, 5-exo-dig cyclization, and a long-range 1,5-acyl migration reaction. Based on this assumption, we envisioned that a novel unconventional 2vinyl-3-oxo-1-methyleneindene ester synthesis could be realized by allowing the plausible reactive metalla-substituted species to react with an active electrophile.[14] We envisioned that application of this migratory protocol to 2-methyl-4-(2-(phenylethynyl)phenyl)but-3-yn-2-yl acetate 1 a under suitable catalytic conditions might first lead to carboxyallene complexes A through a [3.3]-acyloxy migration, and subsequent 5-exo-dig cyclization may form five-membered metalla-containing species B. Next, the alkyl C¢H bond which was attached at the 2-vinylindene position could be selectively activated under the direction of the 3-oxonium carbonyl group, thus facilitating the final long-range 1,5-protodemetallation reaction to give 2-vinyl-3-oxo-1-methyleneindenes acetate 2 a, and simultaneously regenerate the metal catalyst (Scheme 1). Alternatively, the 3-oxonium carbonyl moiety in B might undergo hydrolysis and C-M protonation to give 2-vinyl3-oxo-1-methyleneindenone 2 a’. Although this protocol might seem workable, the following two challenges could exist: (1) The structurally bulky alkyl group might hamper the 5-exodig cyclization process of metalla-complex A and (2) the hydrogen atom might not migrate from the chemically inert alkyl group, thus terminating the whole catalytic transformation. Stimulated by the aforementioned highly interesting targets, we set out to explore this chemistry in detail. We anticipated that our approach would be an excellent surrogate for the preparation of the synthetically versatile 1-methyleneindene aromatic compounds. After extensive survey of the conditions, we found that the cyclization reaction of compound 1 a using 5.0 mol % of PtCl2 in 0.1 m of p-xylene at 60 8C for 12 h provided compound (E)-1-benzylidene-2-(prop-1-en-2-yl)-1H-inden-3-yl
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Scheme 1. Proposed synthetic route for the generation of (E)-2-vinyl-3-oxo1-methyleneindene.
acetate 2 a in 83 % yield under synthetically neutral conditions (Table 1, entry 1).[15] The (E)-configuration of compound 2 a was further supported by 1H-1H COSY and HMQC experiments. This result suggest that the syn-nucleophilic attack of the carboxyallene to the platinum-activated triple bond in complex A should favor the subsequent 5-exo-dig cyclization reaction, thus forming the exocyclic double bond structure of Pt-containing intermediate B.[16] Surprisingly, compound 2 a’ was not observed when 1 a was used as the starting material in our testing reactions. Ag + and Au3 + salts worked also in this reaction, albeit with moderate efficiency (Table 1, entries 2–5). Note that an Table 1. Screening of the reaction conditions.[a]
Entry
Variation of the reaction conditions
Yield [%][a]
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19
Standard conditions AgBF4 (5 mol %) instead of PtCl2 AgOTf (5 mol %) instead of PtCl2 Ph3PAuCl (5 mol %) instead of PtCl2 AuCl3 (5 mol %) instead of PtCl2 Pt(COD)Cl2 (5 mol %) instead of PtCl2 Pt(acac)2 (5 mol %) instead of PtCl2 Pt(PhCN)2Cl2(5 mol %) instead of PtCl2 Under CO (1 atm) atmosphere Under O2 (1 atm) atmosphere H2O (1.0 eq) as additive MeOH (1.0 eq) as additive Toluene (0.1 M) instead of p-xylene THF (0.1 M) instead of p-xylene DCE (0.1 M) instead of p-xylene MeCN (0.1 M) instead of p-xylene DMF (0.1 M) instead of p-xylene PtCl2 (2.5 mol %) p-xylene (0.067 M)
83 31 56 trace 49 trace trace 75 52 69 71 77 72 55 30 n.r. trace 73[b] 36[b]
[a] Reaction conditions: compound 1 a (0.3 mmol), PtCl2 (0.015 mmol), pxylene (3.0 mL), 60 8C, 10–12 h, isolated yield of 2 a. [b] Reaction time = 18 h. DCE = 1,2-dichloroethane; Tf = trifluoromethylsulfonate. Chem. Asian J. 2015, 10, 1463 – 1466
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AuI-complex performed rather sluggish in the current cyclization reaction (Table 1, entry 4).[17] Since a platinum catalyst constantly showed a good reactivity in this type of 1,3-acyloxy/1,5H migration reaction,[13a] we next switched our attention to different types of Pt catalysts. While organometallic complexes such as Pt(COD)Cl2 and Pt(acac)2 were inert for this reaction, a good conversion was observed when Pt(PhCN)2Cl2 was used, and PtCl2 proved to be the optimal catalyst (Table 1, entries 1 and 6–8). A metal-free experiment revealed that no conversion occurred in the reaction, and other PtIV catalysts, including PtPh4 and PtCl4, did not work at all (data not shown). Using carbon monoxide (CO) or dioxygen (O2) did not improve the chemical yield of 2 a (Table 1, entries 9 and 10). Interestingly, unlike our previous Pt-catalyzed 1,5-acyl migration reaction, which was very sensitive to moisture, water did not affect the current transformation;[13a] the product 2 a could be isolated in 71 % or 77 % yield when 1.0 equivalent of proton solvent was added into the reaction system (Table 1, entries 11–12). With respect to the solvent effect, conventional polar solvents such as 1,2-dichloroethane (DCE), MeCN, and DMF were less conducive, presumably due to competitive side reactions (Table 1, entries 13–17). While lowering of the catalyst loading to 2.5 mol % resulted in a prolonged reaction time and a reduced yield of 73 %, diluting the reaction concentration in p-xylene to 0.067 m had a much worse impact on the chemical efficiency (Table 1, entries 18–19). With the optimal conditions as shown (Table 1, entry 1) in hand, the scope of this reaction was then investigated (Table 2). The migratory ability of the acyl moiety (R3CO) in compound 1 (R1 = Me, and R2 = H) was first examined. With the acyl group of 1 a replaced by a propionyl or a cyclohexanecarbonyl group, the reaction proceeded smoothly to afford the desired 2-vinyl-3-oxobenzofulvenes 2 b and 2 c in 63 % and 61 % yield, respectively. Good yields were obtained when aromatic migratory groups (R3) were attached at the carbonyl position. For example, the ester group of R3 with electron-donating (2 e) or weakly electron-withdrawing (2 f–2 i) substituents or no substitution (2 d and 2 j) underwent the reaction smoothly, affording the corresponding products in 66 % to 84 % yields. The structure of compound 2 f was identified unambiguously by X-ray diffraction analysis.[18] In the case of a,b-unsaturated alkenes, while compound 2 k was produced in only 57 % yield using methacryloyl as the migratory acyl group, the reaction proceeded nicely with cinnamoyl (2 l). A heterocyclic furyl group could also be tolerated in this reaction, and the structurally divergent compound 2 m was obtained in 71 % yield. A moderate yield of 47 % could be obtained when the structurally rigid cyclohexyl group was located at the propargyl moiety (2 m), which could be possibly rationalized as a less ratable cyclohexyl loop as compared with the free methyl group. A complex mixture was observed when one methyl group (R1 = R2 = H) was located at the propargyl position of 1 n. On the other hand, the results showed that a chemoselective reaction was observed when methyl and ethyl groups were simultaneously present in the propargyl position of 1 o (R1 = R2 = Me); the dehydrogenative process selectively occurred at the methyl group, and the corresponding
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Communication Table 2. Scope of the 2-vinyl-3-oxo-1-methyleneindenes catalyzed by PtCl2.[a,b]
Table 3. Scope of the substituents in substrates 1.
[a] Reaction conditions: compound 1 (0.3 mmol), PtCl2 (0.015 mmol), pxylene (3.0 mL), 60 8C, 12 h. [b] For 24 h. [c] At 90 8C for 24 h. [d] With H2O (1.0 equiv).
[a] Reaction conditions: compound 1 (0.3 mmol), PtCl2 (0.015 mmol), pxylene (3.0 mL), 60 8C, 10–12 h. Isolated yield. [b] At 60 8C for 12 h, then 80 8C for 6 h. [c] With PtCl2 (10 mol %), 80 8C, 24 h. [d] For 24 h.
product 2 o was isolated in 60 % yield. It is interesting to note that the dehydrogenation selectively occurred at the CH3 group rather than at the CH2CH3 group, since the C¢H bond energy of Me is relatively higher than that of Et. Therefore, this result seems to suggest that the steric effect dominates over the electronic effect in the current long-range 1,5-hydride migration process. We have also tried the substrate 1 p, which possesses a cationic-stabilizing benzyl group at the propargyl position (R1 = Et, R2 = OBn); however, the reaction was very complex, and the starting material 1 p decomposed rapidly under the standard conditions.[19] The effect of the electronic variation in the R4 and R5 position of compound 1 were next examined under the optimized conditions. The reaction displayed excellent functional group compatibility in terms of the substituents which were attached on the aromatic ring or on the alkyl group of 1 (Table 3). For example, the additional hydrogen atom (R4) in the central aromatic ring of compound 1 can be readily displaced by electron-donating groups (MeO or Me) or strong electron-withdrawing groups (CF3O or F), affording the expected 2-vinyl-3Chem. Asian J. 2015, 10, 1463 – 1466
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oxo-1-methyleneindenes (3 a–3 d) in moderate to good yields. The fluoro- and trifluoromethoxyl-substituted benzofulvenes (3 c, 3 d) are particularly noteworthy, as it is well known that fluorinated 1-methyleneindenes usually exhibit interesting physicochemical and biological properties.[13b] Various substitutions, such as methoxy (3 e), methyl (3 f), fluoride (3 g), chloride (3 h), ester (3 i), nitro (3 j), and nitrile (3 k), were introduced into the phenyl group at the R5 position to probe the reactivity and regioselectivity. A five-membered heterocyclic thiophenyl group can be well tolerated in the reaction, and the desired product (3 l) can be isolated in reasonable yield. Even though many aryl groups were readily tolerated, the reaction was apparently sensitive to a steric effect because 3 m, which contains a bulky tert-butyl group, was not obtained. This result indicated that steric congestion has a strong influence on the formation of intermediate B from its precursor species A (Scheme 1). Interestingly, the silyl group could be successfully incorporated; the trimethylsilyl (TMS)-substituted compound 3 n was generated in 68 % yield under the standard conditions. The yield of 3 n could be improved to 74 % when 1.0 equivalent of water was added into the reaction system. To gain insight into the reaction mechanism, the deuterium labeled compound 1 n-d6 was synthesized using [D6]acetone as a building block [Scheme 2, Eq. (1)]. The reaction was highly regioselective since 3 n-d6 was successfully isolated without deuterium loss under the standard conditions. This result demonstrated that the migrated hydrogen atom was derived from the unactivated methyl group and that a regioselective longrange 1,5-H shift process was involved in the key intermediate B (Scheme 1). Furthermore, to clarify the possibility whether the reactive C-Pt bond in species B was protonized by a trace amount of water, we have carried out the cyclization reaction of compound 1 n in the presence of 1.0 equivalent of D2O; the
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Communication Keywords: 1,5-diynyl esters · 1,5-hydride migration · platinum catalysis · rearrangements · regioselective
Scheme 2. Evidence of the regioselective long-range 1,5-hydride migration.
product 3 n was isolated and no deuterium incorporation was detected [Scheme 2, Eq. (2)]. These results revealed that the 1,5-H migration was an intramolecular process and no deuterium scrambling occurred during the process. In conclusion, we have developed an efficient and regioselective synthesis of (E)-2-vinyl-3-oxo-1-methyleneindenes through a platinum-catalyzed sequential 1,3-acyloxy migration/ pentannulation/long-range 1,5-hydride migration reaction under neutral and mild conditions. The deuterium labeling experiments clearly established the reaction pathway via the key intermediate B and an intramolecular long-range 1,5-proto-deplatinalation process. We therefore expect that this unusual 1,5-H migration mode opens up new opportunities in the search for unactivated alkyl C¢H activation reactions. Further studies on the application of this novel synthetic protocol can be envisioned and are being explored in the group.
Experimental Section Standard procedure for the synthesis of 2-vinyl-3-oxo-1methyleneindenes 2 a. A 25 mL Schlenk tube equipped with a Teflon-coated magnetic stir bar was charged with PtCl2 (5 mol %, 0.03 mmol), compound 1 a (0.3 mmol, 1.0 equiv), and 3.0 mL of anhydrous p-xylene. The reaction was stirred at 60 8C for 12 h. After completion of the reaction as indicated by TLC, the mixture was cooled to room temperature, diluted with ethyl acetate, and extracted with water. The organic phase was collected and washed with saturated NaCl (aq.), dried over anhydrous Na2SO4, and concentrated. The residue was purified by column chromatography on silica gel (petroleum ether/ ethyl acetate, 200:1) to give the corresponding pure product 2 a.
Acknowledgements We thank the National Natural Science Foundation of China (21462022, 21363009), the NSF of Jiangxi Province (20133ACB20008, 20142BAB203005) for financial support. Chem. Asian J. 2015, 10, 1463 – 1466
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[1] For a rencent review: G. Qiu, J. Wu, Synlett 2014, 25, 2703, and the references therein. [2] a) J. Vicente, J. Abad, J. Gil-Rubio, Organometallics 1995, 14, 2677; b) K. Alexander, L. Julien, B. Carsten, Synlett 2004, 2397. [3] a) S. Lin, R. Waymouth, Acc. Chem. Res. 2002, 35, 765; b) H. G. Alt, A. Kçppl, Chem. Rev. 2000, 100, 1205; c) L. Scott, M. Boorum, B. McMahon, S. Hagen, J. Mack, J. Blank, H. Wegner, A. Meijere, Science 2002, 295, 1500; d) M. Boorum, Y. VasilÀv, T. Drewello, L. Scott, Science 2001, 294, 828. [4] A. Cappelli, S. Galeazzi, G. Giuliani, M. Anzini, A. Donati, L. Zetta, R. Mendichi, M. Aggravi, G. Giorgi, E. Paccagnini, S. Vomero, Macromolecules 2007, 40, 3005. [5] For examples, see: a) D. Campolo, T. Arif, C. Borie, D. Mouysset, N. Vanthuyne, J. Naubron, M. Bertrand, M. Nechab, Angew. Chem. Int. Ed. 2014, 53, 3227; Angew. Chem. 2014, 126, 3291; b) S. Ye, J. Wu, Org. Lett. 2011, 13, 5980; c) P. Cordier, C. Aubert, M. Malacria, E. Lacúte, V. Gandon, Angew. Chem. Int. Ed. 2009, 48, 8757; Angew. Chem. 2009, 121, 8913. Radical cyclization: d) S. Kovalenko, S. Peabody, M. Manoharan, R. Clark, I. Alabugin, Org. Lett. 2004, 6, 2457. [6] a) M. Schmittel, C. Vavilala, J. Org. Chem. 2005, 70, 4865; b) G. Bucher, A. Mahajan, M. Schmittel, J. Org. Chem. 2008, 73, 8815. [7] F. W. Patureau, T. Besset, N. Kuhl, F. Glorius, J. Am. Chem. Soc. 2011, 133, 2154. [8] J. Hwang, Y. H. Jung, Y. Hong, S. Jeon, I. Jeong, J. Fluorine Chem. 2011, 132, 1227. [9] a) S. Ye, K. Gao, H. Zhou, X. Yang, J. Wu, Chem. Commun. 2009, 5406; b) S. Ye, H. Ren, J. Wu, J. Comb. Chem. 2010, 12, 670. [10] P. Lee, T. Fujita, N. Yoshikai, J. Am. Chem. Soc. 2011, 133, 17283. [11] a) L. Ye, Y. Wang, D. Aue, L. Zhang, J. Am. Chem. Soc. 2012, 134, 31; b) A. S. K. Hashmi, I. Braun, P. Nosel, J. Schadlich, M. Wieteck, M. Rominger, Angew. Chem. Int. Ed. 2012, 51, 4456; Angew. Chem. 2012, 124, 4532. [12] Myers–Saito cyclization: a) A. G. Myers, E. Y. Kuo, N. S. Finney, J. Am. Chem. Soc. 1989, 111, 8057; b) R. Nagata, H. Yamanaka, E. Okazaki, I. Saito, Tetrahedron Lett. 1989, 30, 4995. [13] a) Z. Chen, X. Jia, J. Huang, J. Yuan, J. Org. Chem. 2014, 79, 10674; b) Q. Xiao, H. Zhu, G. Li, Z. Chen, Adv. Synth. Catal. 2014, 356, 3809; c) Z. Chen, X. Jia, C. Ye, G. Qiu, J. Wu, Chem. Asian J. 2014, 9, 126; d) Z. Chen, M. Zeng, J. Yuan, Q. Yang, Y. Peng, Org. Lett. 2012, 14, 3588. [14] For a recent review: H. Zhu, B. Yan, Y. Cao, Z. Chen, Chin. J. Org. Chem. 2015, 35, 509. [15] For a Pt-catalyzed 3.3-acyloxy migration reaction, see: G. Zhang, V. Catalano, L. Zhang, J. Am. Chem. Soc. 2007, 129, 11358. [16] For theoretical studies on the Pt-catalyzed cycloisomerization of 1,6enynes, see: a) S. Baugmarten, D. Lesage, V. Gandon, J. Goddard, M. Malacria, J. Tabet, Y. Gimbert, L. Fensterbank, ChemCatChem 2009, 1, 138; b) Y. Gimbert, L. Fensterbank, V. Gandon, J. Goddard, D. Lesage, Organometallics 2013, 32, 374. [17] For Au-catalyzed [3.3]-acyloxy migrations, see: a) Y. Chen, M. Chen, Y. Liu, Angew. Chem. Int. Ed. 2012, 51, 6493; Angew. Chem. 2012, 124, 6599; b) D. Lebœuf, A. Simonneau, C. Aubert, M. Malacria, V. Gandon, L. Fensterbank, Angew. Chem. Int. Ed. 2011, 50, 6868; Angew. Chem. 2011, 123, 7000; c) J. Zhao, C. O. Hughes, F. D. Toste, J. Am. Chem. Soc. 2006, 128, 7436. [18] CCDC 1040967 (2 f) contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_ request/cif. [19] B. Bolte, Y. Odabachian, F. Gagosz, J. Am. Chem. Soc. 2010, 132, 7294. Manuscript received: March 12, 2015 Accepted article published: April 30, 2015 Final article published: May 27, 2015
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