Highly Chemoselective CarbonCarbon σ‐Bond Activation: Nickel/Lewis Acid Catalyzed Polyfluoroarylcyanation of Alkynes

Abstract

Selective CC bond cleavage: A catalyst consisting of nickel(0)/DPEphos and BPh3 is highly effective for the addition of polyfluorobenzonitriles to alkynes through selective activation of the CCN bond over the CH or CF bonds. The addition reaction is applicable to the sequential insertion of two different alkynes into CCN and CH bonds (see scheme). Metal-catalyzed activation of saturated CC bonds has a great potential in economical and ecofriendly transformations.1 For example, the reaction involving cleavage of the CC σ bond and subsequent addition to unsaturated bonds is ideal for the simultaneous formation of two CC σ bonds without the generation of by-products (100 % atom economy). On the other hand, CF and CH activation of polyfluoroarenes by various metal complexes has been well investigated for synthetic organic chemistry.2, 3 However, the catalytic functionalization of polyfluoroarenes through CC activation remains to be explored. In this respect, the work by Gunay and Jones is seminal: the C(sp1)C6F5 bond in bis(pentafluorophenyl)acetylene is shown to add oxidatively to a platinum(0) complex under UV irradiation.4 Our group demonstrated that the nickel(0)/Lewis acid catalyst system is highly effective for the carbocyanation of alkynes and alkenes using various organic nitriles.1b, 5 On the basis of these studies, we expected that CCN activation by nickel(0)/Lewis acid catalyst is preferred rather than CH and CF activation. Herein, we report the selective cleavage of the CCN bond in polyfluorobenzonitriles by the nickel(0)/DPEphos complex (DPEphos=bis(2-diphenylphosphinophenyl)ether) and BPh3; all other reactive CH and CF bonds are unaffected, thus resulting in the smooth addition of the polyfluorophenyl and cyano moieties to CC and CC bonds. Time course of the competition reaction between 1 a and 4 catalyzed by [Ni(cod)2], DPEphos, and BPh3. •: yield of 3 aa. ▴: yield of 5. ORTEP diagram of cis-7 a (top) and trans-7 b (bottom). With the information obtained by the mechanistic analysis, we examined the scope of the polyfluorobenzonitriles under the optimum conditions (Table 1). The reaction of 2,3,4,5-tetrafluorobenzonitrile 1 c with 2 a proceeded smoothly to give 3 ca in 98 % yield (Table 1, entry 1). Mono-, di-, and trifluorobenzonitriles 1 d–1 j gave the corresponding adducts 3 da–3 ja in over 90 % yield (Table 1, entries 2–8). Ent. 1 Yield [%][b] Ent. 1 Yield [%][b] 1 1 c 3 ca, 98 5 1 g 3 ga,90 2[c] 1 d 3 da, 98 3 1 e 3 ea, 98 6 7 8 1 h 1 i 1 j o-F m-F p-F 3 ha, 97 3 ia, 98 3 ja, 98 4 1 f 3 fa, 97 9[d] 1 k 3 ka, 93 Similarly, 2,3,5,6-tetrafluoro-4-pyridinecarbonitrile 1 k reacted smoothly with 2 a to give 3 ka in 93 % yield, although a stoichiometric amount of BPh3 was required for this conversion. A catalytic amount of BPh3 failed to promote the reaction, possibly because the nitrogen atom in the polyfluoropyridyl group lowered the Lewis acidity of BPh3 throught coordination (Table 1, entry 9). Using 1 c as the substrate, we examined the scope of the alkynes (Table 2). Symmetrical alkynes, such as 3-hexyne 2 b, bis(trimethylsilylmethyl)acetylene 2 c, and diphenylacetylene 2 d, gave the corresponding adducts 3 cb, 3 cc, and 3 cd in good yields (Table 2, entries 1–3). 1-Phenyl-1-propyne 2 e gave the corresponding adducts 3 ce and 3 ce′ in 87 % combined yield with poor selectivity (54:46); this result stands in sharp contrast to that observed for the arylcyanation of 1-(4-methoxyphenyl)-1-butyne with 4-chlorobenzonitrile (Table 2, entry 4).5d, 13 The structures of 3 cd and 3 ce′ were unambiguously established by X-ray crystallographic analysis.9 4,4-Dimethyl-2-pentyne 2 f gave 3 cf and 3 cf′ in 86:14 ratio, demonstrating that the CN group prefers a more-hindered alkyne carbon center, similar to the arylcyanation reaction (Table 2, entry 5).5d Of note, the addition of 1 c to triisopropylsilylacetylene 2 g gave 3 cg with excellent regioselectivity, albeit in modest yield (Table 2, entry 6). Presumably, the use of DPEphos, which is a weak donor ligand, and/or an electron-withdrawing polyfluoroaryl group allows the polyfluoroarylcyanation of terminal alkynes. Facile trimerization and oligomerization of terminal alkynes are prone to take place in the presence of nickel catalysts with electron-donating phosphine ligands, as described in the previous carbocyanation results.5d Entry R1, R2 (2) t [h] Product Yield [%][b] 3:3′[c] 1 Et, Et (2 b) 8 87 3 cb 2 CH2TMS, CH2TMS (2 c) 26 72 3 cc 3[d] Ph (2 d) 23 71 3 cd 4[e] Me, Ph (2 e) 8 87 54:46 3 ce (E/Z=4:96), 3 ce′ 5[f] Me, tBu (2 f) 52 83 86:14 3 cf, 3 cf′ 6 H, TIPS (2 g) 24 55 >99:1 3 cg A plausible mechanism for the reaction of polyfluorobenzonitrile with an alkyne is shown in Scheme 1. The catalytic reaction should be initiated by the formation of the η2-complex 12 or 12′. Subsequent oxidative addition of the CCN bond to nickel(0) affords 13 after the cyano group nitrogen atom is bound to BPh3. Insertion of alkyne 2 into the ArFNi bond in 13 gives 15 via the alkyne-coordinated complex 14. Steric repulsion between the bulkier group R2 and the polyfluorophenyl group on the Ni center in 14 is assumed to be minimal.15 Finally, CC bond-forming reductive elimination of 3 from 15 generates a nickel(0) complex to complete the catalytic cycle. The low regioselectivity in the reaction with 1-phenyl-1-propyne 2 e may be ascribed to a plausible π-stacking interaction between the electron-deficient ArF and the phenyl ring (R1) in 14, followed by arylnickelation toward the alkyne.16 This interaction apparently competes with the regioselectivity caused by the steric repulsion. A plausible mechanism for the reaction of polyfluorobenzonitrile with alkyne. Encouraged by the selective CCN activation of polyfluorobenzonitriles, we examined the orthogonal CH activation of the adducts for the reaction of 3 ba with 2 c (Scheme 2).3a,3c A catalyst system consisting of nickel(0), PCyp3, and BPh3 was effective for the production of the desired hydropolyfluoroarylation product 16 in 90 % yield. The effect of BPh3 remains to be carefully examined, but it is assumed that ligation of the cyano group to the boron atom enhances the reactivity of the CH bond by lowering the electron density of the polyfluoroaryl moiety. In the absence of BPh3, the yield of the double adduct 16 significantly decreased. The feasibility of one-pot sequential CCN and CH activation was also confirmed: 16 was obtained in 72 % yield without isolation of the intermediate 3 ba. Aryl cyanation/hydroarylation of alkynes. In conclusion, the present study has substantiated the role of a nickel/BPh3 catalyst system in the addition of polyfluorobenzonitriles to alkynes through selective CCN activation without CH and CF bond cleavages. This method allows access to a variety of fluorinated organic compounds as functional materials for liquid crystals and organic light-emitting diodes.17, 18 The fluorine atoms bound to the aryl groups significantly enhance the reactivity of the CCN bond toward the oxidative addition to the nickel(0) complex. Site-selective alkenylation between the CCN and CH bond also proceeds successfully. Efforts to extend the present polyfluoroarylcyanation reaction to various other substrates are underway. Detailed facts of importance to specialist readers are published as ”Supporting Information”. Such documents are peer-reviewed, but not copy-edited or typeset. They are made available as submitted by the authors. 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