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[reaction: see text] The enantioselective catalytic 1,4-addition to alpha,beta-unsaturated ketimines is an unprecedented process. Herein, we document the copper-catalyzed addition of dialkylzinc reagents to (2-pyridylsulfonyl)imines of chalcones. This process occurs rapidly in the presence of a chiral phosphoramidite ligand to afford exclusively the 1,4-addition product. In the case of addition of dimethylzinc, enantioselectivities in the range 70-80% ee are obtained. The presence of the metal-coordinating 2-pyridylsulfonyl group proved to be essential for this reaction to proceed.

Because an array of interesting target molecules include ketones that bear an α-aryl substituent, the development of methods for the synthesis of this structural motif has been an active area of investigation.[1] For example, extensive effort has recently been devoted to the discovery of palladium catalysts for the cross-coupling of ketones with aryl halides in the presence of a Bronsted base (path A in eq 1; via an enolate).[2] Furthermore, in the case of α, α-disubstituted ketones, catalytic asymmetric α-arylations have been described wherein quaternary stereocenters are generated with excellent enantioselectivity.[3,4] Unfortunately, these methods cannot be applied to the asymmetric synthesis of more commonly encountered tertiary stereocenters, due to the propensity of α-arylketones such as 1 to enolize under the reaction conditions.[5,6] (1) Alternatively, an umpolung arylation process, whereby a ketone that bears an α leaving group reacts with an arylmetal reagent, could provide the target α-arylketone (path B in eq 1). Until recently, there were no examples of palladium- or nickel-catalyzed cross-couplings between secondary α-halocarbonyl compounds and arylmetals (metal = B, Si, Sn, or Zn). In 2007, we reported that a nickel catalyst can achieve Hiyama arylation reactions with a wide array of electrophiles, including secondary α-halocarbonyl compounds (and Lei later described a nickel-based method for Suzuki couplings).[7] In the case of α-haloesters, we were able to subsequently develop a catalytic asymmetric α-arylation process that furnishes tertiary stereocenters (eq 2; TBAT = [F2SiPh3]−[NBu4).[8] However, we could not apply this method to corresponding Hiyama arylations of α-haloketones, presumably due to the Bronsted-basic reaction conditions.[9,10] (2) Unlike cross-coupling processes such as the Hiyama and Suzuki reactions, which often employ Lewis/Bronsted-basic activators, the Negishi reaction typically proceeds without an additive,[11,12] thereby making it an attractive starting point for the development of a method for the catalytic asymmetric α-arylation of ketones to generate (potentially labile) tertiary stereocenters. In this report, we establish that a nickel/pybox catalyst can indeed achieve enantioselective cross-couplings of racemic α-bromoketones with arylzinc reagents under very mild conditions in good ee and yield (eq3).[13,14] (3) The data in Table 1 illustrate the role that various reaction parameters play in determining the efficiency of this stereoconvergent Negishi α-arylation of ketones. Thus, no cross-coupling occurs if NiCl2·glyme is omitted (Table 1, entry 2), whereas carbon-carbon bond formation does proceed in the absence of ligand 2[15] (Table 1, entry 3). Pybox ligands other than 2 furnish lower ee and yield (Table 1, entries 4 and 5), as do solvents other than a glyme/THF mixture (Table 1, entries 6–8). At room temperature, the catalyst system is somewhat less effective than at −30 °C (Table 1, entry 9). Table 1 Catalytic asymmetric arylations of racemic α-bromoketones: Effect of reaction parameters With our optimized method, we can achieve Negishi cross-couplings of racemic 2-bromopropiophenone with an array of arylzinc reagents in excellent ee and good yield (Table 2)[16] although the efficiency of the process is sensitive to the steric demand of the nucleophile (Table 2, entry 2). The organozinc can include a range of functional groups, such as OR, halogen, NR2, and SR. Diarylzinc reagents (Ar2Zn) and arylzinc iodides (ArZnl) generally furnish similar enantioselectivities and yields (e.g., Table 2, entry 1)[17] The α-arylated ketone is stable to racemization under these conditions. Table 2 Catalytic asymmetric arylations of racemic α-bromoketones: Variation of the nucleophile We have examined the scope of this method for the catalytic asymmetric α-arylation of ketones not only with respect to the nucleophile (Table 2), but also the electrophile (Table 3). Very good ee’s and useful yields are observed with a variety of α-alkyl substituents, including those that are functionalized (Table 3, entries 2 and 3) and β-branched (Table 3, entry 4); however, if R is large, little of the cross-coupling product is formed (Table 3, entry 5). If the aryl group of the ketone is bulky, the reaction proceeds with moderate enantioselectivity (Table 3, entries 6 and 7). On the other hand, good ee’s are observed regardless of whether the group is electron-rich (Table 3, entry 8) or electron-poor (Table 3, entry 9). A thiophene is compatible with this nickel-based coupling process (Table 3, entry 10).[18] Table 3 Catalytic asymmetric arylations of racemic α-bromoketones: Variation of the electrophile In conclusion, we have developed the first catalytic asymmetric method for cross-coupling arylmetal reagents with α-haloketones, specifically, the NiCl2·glyme/2-catalyzed reaction of arylzincs with racemic secondary α-bromoketones. This stereoconvergent carbon–carbon bond-forming process occurs under unusually mild conditions (−30 °C and no activators), thereby allowing the generation of potentially labile tertiary stereocenters. Ongoing efforts are directed at further expanding the scope of cross-coupling reactions of alkyl electrophiles.

Because an array of interesting target molecules include ketones that bear an α-aryl substituent, the development of methods for the synthesis of this structural motif has been an active area of investigation.[1] For example, extensive effort has recently been devoted to the discovery of palladium catalysts for the cross-coupling of ketones with aryl halides in the presence of a Bronsted base (path A in eq 1; via an enolate).[2] Furthermore, in the case of α, α-disubstituted ketones, catalytic asymmetric α-arylations have been described wherein quaternary stereocenters are generated with excellent enantioselectivity.[3,4] Unfortunately, these methods cannot be applied to the asymmetric synthesis of more commonly encountered tertiary stereocenters, due to the propensity of α-arylketones such as 1 to enolize under the reaction conditions.[5,6] (1) Alternatively, an umpolung arylation process, whereby a ketone that bears an α leaving group reacts with an arylmetal reagent, could provide the target α-arylketone (path B in eq 1). Until recently, there were no examples of palladium- or nickel-catalyzed cross-couplings between secondary α-halocarbonyl compounds and arylmetals (metal = B, Si, Sn, or Zn). In 2007, we reported that a nickel catalyst can achieve Hiyama arylation reactions with a wide array of electrophiles, including secondary α-halocarbonyl compounds (and Lei later described a nickel-based method for Suzuki couplings).[7] In the case of α-haloesters, we were able to subsequently develop a catalytic asymmetric α-arylation process that furnishes tertiary stereocenters (eq 2; TBAT = [F2SiPh3]−[NBu4).[8] However, we could not apply this method to corresponding Hiyama arylations of α-haloketones, presumably due to the Bronsted-basic reaction conditions.[9,10] (2) Unlike cross-coupling processes such as the Hiyama and Suzuki reactions, which often employ Lewis/Bronsted-basic activators, the Negishi reaction typically proceeds without an additive,[11,12] thereby making it an attractive starting point for the development of a method for the catalytic asymmetric α-arylation of ketones to generate (potentially labile) tertiary stereocenters. In this report, we establish that a nickel/pybox catalyst can indeed achieve enantioselective cross-couplings of racemic α-bromoketones with arylzinc reagents under very mild conditions in good ee and yield (eq3).[13,14] (3) The data in Table 1 illustrate the role that various reaction parameters play in determining the efficiency of this stereoconvergent Negishi α-arylation of ketones. Thus, no cross-coupling occurs if NiCl2·glyme is omitted (Table 1, entry 2), whereas carbon-carbon bond formation does proceed in the absence of ligand 2[15] (Table 1, entry 3). Pybox ligands other than 2 furnish lower ee and yield (Table 1, entries 4 and 5), as do solvents other than a glyme/THF mixture (Table 1, entries 6–8). At room temperature, the catalyst system is somewhat less effective than at −30 °C (Table 1, entry 9). Table 1 Catalytic asymmetric arylations of racemic α-bromoketones: Effect of reaction parameters With our optimized method, we can achieve Negishi cross-couplings of racemic 2-bromopropiophenone with an array of arylzinc reagents in excellent ee and good yield (Table 2)[16] although the efficiency of the process is sensitive to the steric demand of the nucleophile (Table 2, entry 2). The organozinc can include a range of functional groups, such as OR, halogen, NR2, and SR. Diarylzinc reagents (Ar2Zn) and arylzinc iodides (ArZnl) generally furnish similar enantioselectivities and yields (e.g., Table 2, entry 1)[17] The α-arylated ketone is stable to racemization under these conditions. Table 2 Catalytic asymmetric arylations of racemic α-bromoketones: Variation of the nucleophile We have examined the scope of this method for the catalytic asymmetric α-arylation of ketones not only with respect to the nucleophile (Table 2), but also the electrophile (Table 3). Very good ee’s and useful yields are observed with a variety of α-alkyl substituents, including those that are functionalized (Table 3, entries 2 and 3) and β-branched (Table 3, entry 4); however, if R is large, little of the cross-coupling product is formed (Table 3, entry 5). If the aryl group of the ketone is bulky, the reaction proceeds with moderate enantioselectivity (Table 3, entries 6 and 7). On the other hand, good ee’s are observed regardless of whether the group is electron-rich (Table 3, entry 8) or electron-poor (Table 3, entry 9). A thiophene is compatible with this nickel-based coupling process (Table 3, entry 10).[18] Table 3 Catalytic asymmetric arylations of racemic α-bromoketones: Variation of the electrophile In conclusion, we have developed the first catalytic asymmetric method for cross-coupling arylmetal reagents with α-haloketones, specifically, the NiCl2·glyme/2-catalyzed reaction of arylzincs with racemic secondary α-bromoketones. This stereoconvergent carbon–carbon bond-forming process occurs under unusually mild conditions (−30 °C and no activators), thereby allowing the generation of potentially labile tertiary stereocenters. Ongoing efforts are directed at further expanding the scope of cross-coupling reactions of alkyl electrophiles.

A convenient and efficient synthesis of 3,5-di(trimethylsilylethynyl)phenylacetylene and p-[3,5-di(trimethylsilylethynyl)-1-phenylethynyl]phenylacetylene and the naphthylethynyl homologues terminal acetylenes of 5-(N,N-dimethylamino)naphthylethyne have been carried out. These terminal acetylene compounds serve to prepare nanometer-sized conjugated 1,3,5-tri(ethynylphenyl)benzene and 1,3,5-tri(ethynylnaphthyl)benzene oligomers, by means of heterocoupling with 1,3,5-triiodobenzene, catalysed by palladium, in excellent yields. Both the ethynylphenyl or ethynylnaphthyl homologues chains show fluorescence emission radiation, with important quantum yield.