Nickel-catalyzed reductive coupling of alkynes and epoxides

Nickel-catalyzed, intramolecular and intermolecular reductive coupling of alkynes and epoxides affords synthetically useful homoallylic alcohols of defined alkene geometry. Very high regioselectivity is generally observed, and cyclizations proceed with complete selectivity for endo epoxide opening. This catalytic reaction represents the first use of a non-pi-based electrophile in a growing class of nickel-catalyzed, multicomponent coupling reactions, and is the first catalytic method of reductive coupling of alkynes and epoxides that is effective for both intermolecular and intramolecular cases, and mechanistically distinct from these, possibly involving a nickella(II)oxetane.     

Regioselectivity in intermolecular Pauson-Khand reactions of dissymmetric fluorinated alkynes

Stoichiometric and catalytic intermolecular Pauson-Khand reactions (PKRs) of dissymmetric fluorinated alkynes were performed, affording regioselectively α-fluorinated cyclopentenones. Ethyl 4,4,4-trifluorobutynoate was an excellent substrate; its reaction with norbornadiene gave the corresponding PKR adduct in good yield and complete regioselectivity. Conjugate addition of nitroalkanes or cyanide to this adduct is stereospecific and entails concomitant loss of a trifluoromethyl group. This reaction can be exploited to prepare cyclopentenones featuring quaternary centers.     

Regioselectivity studies of sydnone cycloaddition reactions of azine-substituted alkynes

The synthesis of azine-substituted pyrazoles by a sydnone cycloaddition strategy is described. Incorporation of a 3-pyridyl moiety at the sydnone N-atom has little effect on either reactivity or regioselectivity, however, 2-ethynyl-pyridine and -pyrimidine undergo cycloaddition with surprisingly poor levels of regiocontrol. A rationale for the observed regiochemical trends and potential routes for improving selectivities are discussed.     

Cobalt-catalyzed reductive coupling of activated alkenes with alkynes

Cobalt complex/Zn systems effectively catalyze the reductive coupling of activated alkenes with alkynes in the presence of water to give substituted alkenes with very high regio- and stereoselectivity in excellent yields. While the intermolecular reaction of acrylates, acrylonitriles, and vinyl sulfones with alkynes takes place in the presence of CoI2(PPh3)2/Zn, the reaction of enones and enals with alkynes requires the use of the CoI2(dppe)/Zn/ZnI2 system. The intramolecular reductive coupling of activated alkenes (enones, enals, acrylates, and acrylonitriles) with alkynes also works efficiently. Further a variety of cyclic lactones and lactams were prepared using this methodology. Possible mechanistic pathways are proposed based on a deuterium-labeling experiment carried out in the presence of D2O.     

Radical-type reactions in protic and aprotic media: Comparisons in nickel-catalysed electrochemical reductive cyclisations

The electrochemical reductive cyclisation of unsaturated organic halides in the presence of Ni(II) complexes as catalysts was examined in aprotic solvents such as DMF and in protic solvents such as ethanol, butanol or ethanol–water mixtures. The presence of the alcohol media enhanced the rate of recycling of the catalytic species.     

Highly selective catalytic intermolecular reductive coupling of alkynes and aldehydes

Alkynes (internal and terminal) and aldehydes (aromatic and aliphatic) are reductively coupled in a single catalytic reaction to yield di- and trisubstituted allylic alcohols with high stereoselectivity and regioselectivity. In most cases, a 1:1 ratio of alkyne to aldehyde is sufficient for efficient coupling. The yield and regioselectivity are strongly dependent on the phosphine ligand, but the allylic alcohols formed are invariably the products of cis addition to the alkyne.     

Regioselective reductive coupling of alkynes and aldehydes leading to allylic alcohols

Treatment of a mixture of a terminal alkyne and an aldehyde with CrCl(2) and a catalytic amount of NiCl(2) and triphenylphosphine in the presence of water in DMF at 25 degrees C gives a 1,2-disubstituted allylic alcohol regioselectively.     

Carbon dioxide mediated stereoselective copper-catalyzed reductive coupling of alkynes and thiols

A simple protocol for the stereoselective copper-catalyzed hydrothiolation of alkynes under a CO(2) atmosphere has been developed. The stereoselectivity is determined by the presence/absence of a CO(2) atmosphere. The reaction system is robust and utilizes inexpensive, readily available substrates. A cyclic alkene/carboxylate copper complex intermediate is proposed as the key step in determining the stereoselectivity, and an equivalent amount of water is found to play an active role as a proton donor.     

anti-1,2-Diols via Ni-catalyzed reductive coupling of alkynes and alpha-oxyaldehydes

[reaction: see text] Ni-catalyzed reductive coupling of aryl alkynes (1) and enantiomerically enriched alpha-oxyaldehydes (2) afford differentiated anti-1,2-diols (3) with high diastereoselectivity and regioselectivity, despite the fact that the methoxymethyl (MOM) and para-methoxybenzyl (PMB) protective groups typically favor syn-1,2-diol formation in carbonyl addition reactions of this family of aldehydes.     

Regioselectivity in the Stille coupling reactions of 3,5-dibromo-2-pyrone

The Stille couplings of 3,5-dibromo-2-pyrone normally take place regioselectively at C3, lower in electron density than C5, thus oxidative addition proceeds faster . When the reactions are carried out with Cu(I) in DMF or other polar aprotic solvent, however, the couplings occur predominantly at C5. The observed regiochemical reversal is attributed to the preferred formation of 5-pallado-2-pyrone intermediate which, in addition, turned out to be more reactive than 3-pallado-2-pyrone intermediate.     

Cobalt-catalyzed highly regio- and stereoselective intermolecular reductive coupling of alkynes with conjugated alkenes

In the presence of Co(PPh3)2I2, PPh3, water, and zinc powder, the reaction of alkynes (R1CCR2: R1 = Ph, R2 = Me (1a); R1 = Ph, R2 = Ph (1b); R1 = Et, R2 = Et (1c); R1 = Ph, R2 = (CH2)3OH (1d); R1 = CO2Et, R2 = Ph (1e); R1 = CO2Me, R2 = (CH2)4CH3 (1f); R1 = CO2Et, R2 = SiMe3 (1g)) with alkenes having an electron-withdrawing substituent (CH2=CHR: R = CO2Bu (2a), CN (2b), SO2Ph (2c) and CO2Me (2d)) proceeded smoothly in acetonitrile to give the corresponding reductive coupling products (R1HC=CR2CH2CH2R, 3a-j) in fair to excellent yields. This reductive coupling is highly regio- and stereoselective; only one isomer was observed for each reaction. The results of an isotope-labeling experiment using D2O (99%) to replace normal water for the reductive coupling of vinyl phenyl sulfone 2c with alkyne 1a revealed that the product is E-Ph(D)C=CMeCH2CH(D)SO2Ph deuterated at the olefinic proton and one of the protons of the alpha-methylene group in 84 and 96%, respectively. Possible mechanisms for this highly regio- and stereoselective ene-yne catalytic reaction are proposed.     

Formal hydrochromination of alkynes under nickel catalysis. Regioselective reductive coupling of alkynes and aldehydes leading to allylic alcohols

Formal hydrochromation of an alkyne leading to a 1-substituted ethenylchromium reagent is accomplished by addition of the alkyne and water to a mixture of low-valent chromium(II), a catalytic amount of nickel(II), and triphenylphosphine in DMF.     

Highly enantioselective direct reductive coupling of conjugated alkynes and alpha-ketoesters via rhodium-catalyzed asymmetric hydrogenation

Catalytic hydrogenation of 1,3-enynes 1a-7a in the presence of ethyl pyruvate and related activated ketones using chirally modified cationic rhodium catalysts results in reductive coupling to afford dienylated alpha-hydroxy esters 1b-7b and 3c-3f with exceptional levels of regio- and enantiocontrol. These studies represent the first highly enantioselective direct catalytic reductive couplings of alkynes to ketones. As illustrated by the conversion of 6b to 6c-6h, the diene containing the side chain of the coupling products is subject to diverse chemo- and regioselective manipulation. Reductive coupling of enyne 6a and ethyl pyruvate using elemental deuterium provides the monodeuterated product deuterio-6b, consistent with a catalytic mechanism involving alkyne-carbonyl oxidative coupling followed by hydrogenolytic cleavage of the resulting oxametallacycle, as corroborated by ESI-MS analysis.     

Regioselectivity of Birch reductive alkylation of biaryls

[reaction: see text] The regioselectivity of the Birch reductive alkylation of polysubstituted biaryls has been investigated. Results indicate that regioselectivity is affected by the electronic nature of substituents on both aromatic rings. The electron-rich 3,5-dimethoxyphenyl moiety is selectively reduced and then alkylated, while phenols and aniline are not dearomatized under these conditions. Biaryls possessing a phenol moiety are alkylated on the second ring, providing that the acidic proton has been removed prior to the Li/NH3 reduction.     

Amido pincer complex of nickel-catalysed Kumada cross-coupling reactions

Novel nickel complexes bearing P,N,P-, P,N,N- and N,N,N-amido pincer ligands exhibited highly catalytic activity in Kumada coupling reactions.     

Ni(II) salts and 2-propanol effect catalytic reductive coupling of epoxides and alkynes

A Ni-catalyzed reductive coupling of alkynes and epoxides using Ni(II) salts and simple alcohol reducing agents is described. Whereas previously reported conditions relied on Ni(cod)(2) and Et(3)B, this system has several advantages including the use of air-stable and inexpensive Ni(II) precatalysts (e.g., NiBr(2)·3H(2)O) as the source of Ni(0) and simple alcohols (e.g., 2-propanol) as the reducing agent. Deuterium-labeling experiments are consistent with oxidative addition of an epoxide C-O bond that occurs with inversion of configuration.     

DFT insight into asymmetric alkyl–alkyl bond formation via nickel-catalysed enantioconvergent reductive coupling of racemic electrophiles with olefins

A DFT study has been conducted to understand the asymmetric alkyl–alkyl bond formation through nickel-catalysed reductive coupling of racemic alkyl bromide with olefin in the presence of hydrosilane and K₃PO₄. The key findings of the study include: (i) under the reductive experimental conditions, the Ni(ii) precursor is easily activated/reduced to Ni(0) species which can serve as an active species to start a Ni(0)/Ni(ii) catalytic cycle. (ii) Alternatively, the reaction may proceed via a Ni(i)/Ni(ii)/Ni(iii) catalytic cycle starting with a Ni(i) species such as Ni(i)–Br. The generation of a Ni(i) active species via comproportionation of Ni(ii) and Ni(0) species is highly unlikely, because the necessary Ni(0) species is strongly stabilized by olefin. Alternatively, a cage effect enabled generation of a Ni(i) active catalyst from the Ni(ii) species involved in the Ni(0)/Ni(ii) cycle was proposed to be a viable mechanism. (iii) In both catalytic cycles, K₃PO₄ greatly facilitates the hydrosilane hydride transfer for reducing olefin to an alkyl coupling partner. The reduction proceeds by converting a Ni–Br bond to a Ni–H bond via hydrosilane hydride transfer to a Ni–alkyl bond via olefin insertion. On the basis of two catalytic cycles, the origins for enantioconvergence and enantioselectivity control were discussed.

The enantioconvergent alkyl–alkyl coupling involves two competitive catalytic cycles with nickel(0) and nickel(i) active catalysts, respectively. K₃PO₄ plays a crucial role to enable the hydride transfer from hydrosilane to nickel–bromine species.     

Nickel-catalyzed reductive electrocarboxylation of disubstituted alkynes

Electrochemically reduced Ni(bipy)₃(BF₄)₂ catalyzes the reaction of carbon dioxide with disubstituted alkynes to yield mono- and di-carboxylated derivatives. The reaction is performed under mild conditions in an undivided cell fitted with a sacrificial magnesium anode.     

Regioselectivity in arene-catalyzed reductive lithiation of acetals of chlorobenzaldehydes

The regioselectivity of arene-catalyzed reductive lithiation of acetals of chlorobenzaldehydes strongly depends on the form of lithium metal employed as a reducing agent. According to previous findings, naphthalene catalyzed reductions run in the presence of lithium powder (high Na content) led to competitive metalations of both aromatic carbon-chlorine and benzylic carbon-oxygen bonds. At variance with these results, naphthalene catalyzed reductions run in the presence of lithium wire (either high or low Na content) led to highly regioselective metalation of aromatic carbon-chlorine bonds. These results disclose new possibilities of selective applications of arene-catalyzed reductive lithiation reactions.