Multicomponent Reactions DOI: 10.1002/ange.200902006 Nickel-Catalyzed Three-Component [2+2+2] Cycloaddition Reaction of Arynes, Alkenes, and Alkynes** Zaozao Qiu and Zuowei Xie* Transition-metal-mediated cycloadditions of alkynes and alkenes serve as a powerful strategy to construct a wide range of compounds, since complexation of the metal center to an olefin or alkyne significantly modifies the reactivity of this moiety. [1] Arynes, a class of very reactive analogues of alkynes, have recently been reported to undergo metal- catalyzed conversion. [2–11] For example, the cyclotrimerization of arynes [2] and the cocyclization of arynes with alkynes, [3] allylic halides, [4] or activated alkenes [5] can all be catalyzed by palladium. Palladium can also catalyze three-component cross-coupling reactions of arynes, allylic halides [6] (allylic epoxides [7] and aromatic halides [8] ), and alkynyl stannanes [6a] (boronic acids [6b] ) to form substituted benzenes, and three- component cyclization of arynes, aryl halides, and alkynes [9] or alkenes [10] to produce phenanthrene derivatives. In contrast, nickel-catalyzed transformations of arynes are much less explored. [11] Very recently, we reported the nickel-mediated three- component [2+2+2] cycloaddition of carboryne with acti- vated alkenes and alkynes to give dihydrobenzocarboranes. [12] In view of the similar reactivity pattern between carboryne and benzyne, [13] we extended our research to include arynes and found that nickel can efficiently catalyze three-compo- nent [2+2+2] cyclization of arynes, alkenes, and alkynes to afford a series of substituted dihydronaphthalenes that cannot be prepared from readily available starting materials. [14] These new findings are reported herein. In an initial attempt, a solution of benzyne precursor 1a (1 equiv, 2-(trimethylsilyl)phenyltriflate), methyl acrylate 2a (2 equiv), and diphenylacetylene 3a (1.2 equiv) in CH 3 CN in the presence of [Ni(cod) 2 ] (cod = 1,5-cyclooctadiene; 10 mol %) and CsF (3 equiv) was stirred at room temperature for 5 h to give the cyclization product 4a in 72 % yield (Table 1, entry 6). Subsequent work focused on optimization of this reaction (Table 1). Changing the ligand from cod to PPh 3 or adding PPh 3 to [Ni(cod) 2 ] led to a large decrease in the yield of isolated 4a from 72 % to 50% (Table 1, entries 1 and 9). Addition of bidentate ligand dppe (dppe = 1,2- bis(diphenylphosphino)ethane) further decreased the yield of isolated 4a to 21% (Table 1, entry 10). No detectable amount of 4a was observed when [NiCl 2 (PnBu 3 ) 2 ]/Zn or [NiCl 2 (dppp)]/Zn (dppp = 1,3-bis(diphenylphosphino)pro- pane) was used as catalyst (Table 1, entries 3 and 5). In contrast, palladium complexes such as [Pd(dba) 2 ] (dba = dibenzylideneacetone), [PdCl 2 (PPh 3 ) 2 ]/Zn, and [Pd(PPh 3 ) 4 ] did not mediate three-component benzyne–alkene–alkyne cyclization; rather, they catalyzed two-component benzyne– alkene–benzyne cycloaddition and cross-coupling [15] to afford 9,10-dihydrophenanthrene 5a and methyl 3-(1,1’-biphenyl-2- yl)-2-propenate 6a (Table 1, entries 11–13). These results showed that 1) both the metal and ligand have a significant effect on the reactions; 2) activated alkene is more reactive than alkyne, otherwise two-component benzyne–alkyne– benzyne cycloaddition products should be observed; and 3) [Ni(cod) 2 ] exhibited the highest catalytic activity in three- component [2+2+2] cyclization. The same results were observed when the catalyst loading was decreased from 10 mol % to 5 mol % (Table 1, entry 8) or the reaction Table 1: Optimization of the three-component cycloaddition reaction. [a] Entry Catalyst Loading [mol %] Yield of 4a [%] [b] (4a :5a :6a) [c] 1 [Ni(PPh 3 ) 4 ] 10 50 (55: < 2:43) 2 [NiCl 2 (PPh 3 ) 2 ]/Zn (1:3) 10 52 (67:8:25) 3 [NiCl 2 (PnBu 3 ) 2 ]/Zn (1:3) 10 0(< 2:51:47) 4 [NiCl 2 (dppe)]/Zn (1:3) 10 11 (17:32:51) 5 [NiCl 2 (dppp)]/Zn (1:3) 10 0(< 1:27:72) 6 [Ni(cod) 2 ] 10 72 (90: < 5: < 5) 7 [Ni(cod) 2 ] 10 73 [d] (90: < 5: < 5) 8 [Ni(cod) 2 ] 5 72 (90: < 5: < 5) 9 [Ni(cod) 2 ]/PPh 3 (1:2) 10 51 (55: < 2:43) 10 [Ni(cod) 2 ]/dppe (1:1) 10 21 (23:16:61) 11 [Pd(dba) 2 ] 10 0(< 2:37:61) 12 [PdCl 2 (PPh 3 ) 2 ]/Zn (1:3) 10 0(< 2:52:46) 13 [Pd(PPh 3 ) 4 ] 10 0(< 1:88:11) [a] Conditions: 1a (0.3 mmol), 2a (0.6 mmol), 3a (0.36 mmol), and CsF (0.9 mmol) in CH 3 CN (1 mL) at room temperature for 5 h. [b] Yields of isolated 4a. [c] Ratio determined by 1 H NMR spectroscopy on the crude product mixture. [d] The reaction was carried out at 50 8C. [*] Z. Qiu, Prof. Dr. Z. Xie Department of Chemistry and Center of Novel Functional Molecules The Chinese University of Hong Kong Shatin, N.T., Hong Kong (China) Fax: (+ 852) 2603-5057 E-mail: zxie@cuhk.edu.hk [**] This work was supported by grants from the Research Grants Council of the Hong Kong Special Administration Region (Project No. 404108) and the Chinese University of Hong Kong. Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/anie.200902006. Angewandte Chemie 5839 Angew. Chem. 2009, 121, 5839 –5842  2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim