Benzylic Electrophiles Research Articles

ChemInform Abstract: Nickel‐Catalyzed Asymmetric Reductive Cross‐Coupling Between Vinyl and Benzyl Electrophiles.

A Ni-catalyzed asymmetric reductive cross-coupling between vinyl bromides and benzyl chlorides has been developed. This method provides direct access to enantioenriched products bearing aryl-substituted tertiary allylic stereogenic centers from simple, stable starting materials. A broad substrate scope is achieved under mild reaction conditions that preclude the pregeneration of organometallic reagents and the regioselectivity issues commonly associated with asymmetric allylic arylation.

Nickel-catalyzed asymmetric reductive cross-coupling between vinyl and benzyl electrophiles.

A Ni-catalyzed asymmetric reductive cross-coupling between vinyl bromides and benzyl chlorides has been developed. This method provides direct access to enantioenriched products bearing aryl-substituted tertiary allylic stereogenic centers from simple, stable starting materials. A broad substrate scope is achieved under mild reaction conditions that preclude the pregeneration of organometallic reagents and the regioselectivity issues commonly associated with asymmetric allylic arylation.

Recent Developments in Palladium-Catalyzed Asymmetric Intermolecular Heck Reaction

Some important progress has been made in palladium-catalyzed asymmetric intermolecular Heck reaction in re- cent years. The breakthrough was achieved in the use of acyclic olefins, the aryl halide and benzylic electrophiles in asym- metric intermolecular Heck reaction with some newly developed chiral ligands by Jung, Sigman and Zhou groups. Asymmet- ric intermolecular oxidative Heck-type reaction of acyclic α,β-unsaturated carbonyls and boronic acids was realized by Jung group in high enantioselectivity in the presence of chiral NHC-amidate-alkoxide Pd(II) complexes as catalyst. The Heck re- action of acyclic hydroxyl alkenes and allyl alcohol aryldiazonium salts was achieved by Sigman group with a catalyst de- rived from Pd2dba3 and chiral pyridine oxazoline by using a redox-relay strategy, affording β-, γ-, and δ-aryl carbonyl prod- ucts in excellent enantioselectivity. Sigman group also reports a catalytic and enantioselective intermolecular Heck-type reac- tion of trisubstituted-alkenyl alcohols with aryl boronic acids, providing direct access to diverse molecular building blocks containing an enantiomerically enriched quaternary carbon center. The first examples of asymmetric Mizoroki-Heck reaction using benzyl electrophiles was reported by Zhou group with their newly developed phosphoramidite as the optimal chiral ligand. With this strategy, a key intermediate in asymmetric synthesis of (+)-anisomycin was quickly afforded when p-methoxybenzyl trifluoroacetate was adopted as starting material. Zhou group also realized the first Heck reaction of aryl bromides and chlorides with various cyclic olefins in high enantioselectivities with (R)-Xyl-SDP(O) as the ligand. The use of alcoholic solvents and alkylammonium salts were essential to creating cationic aryl-Pd species for enantioselective olefin insertion. Zhou group has also realized desymmetrization of substituted cyclic olefins successfully via asymmetric Heck reac- tion and found that the use of bisphosphine mono oxide as ligand was important. The Heck reaction of substituted cyclopen- tenes gives almost exclusively trans isomers and establishes two stereocenters in high ee. Under the effect of some newly developed chiral ligands, fused carbo- and heterocycles are synthesized in high ee via asymmetric domino cyclizations. The method is applied to a short synthesis of chiral diamine en route to (-)-martinellic acid. Keywords palladium-catalysis; asymmetric catalysis; Heck reaction; intermolecular reaction

Arylation of Racemic Secondary Benzylic Electrophiles by Nickel Catalysis

Arylation of Racemic Secondary Benzylic Electrophiles by Nickel Catalysis

Palladium‐Catalyzed Asymmetric Benzylation of Azlactones

Asymmetric benzylation of prochiral azlactone nucleophiles enables the catalytic introduction of a benzyl group towards the synthesis of α,α-disubstituted amino acids. Herein, we report an enantioselective palladium-catalyzed process using chiral bis(diphenylphosphinobenzoyl)diamine (dppba) ligands. Naphthalene- and heterocycle-based methyl carbonates react with a number of azlactones derived from both natural and unnatural amino acids. Monocyclic benzylic electrophiles, for which the barrier to ionization is higher, must employ a phosphate leaving group in order to react. Reaction conditions for electron-rich and -neutral benzylic electrophiles have been developed, and the scope of the reaction has been explored with respect to both reaction partners. The high levels of asymmetric induction, as well as the reactivity pattern of the electrophiles, suggest an η(3)-benzyl intermediate that arises through two distinct pathways.

ChemInform Abstract: Palladium‐Catalyzed, Asymmetric Mizoroki—Heck Reaction of Benzylic Electrophiles Using Phosphoramidites as Chiral Ligands.

AbstractFor the first time the scalable title reaction is reported by using a new phosphoramidite.

β‐Aryl Nitrile Construction via Palladium‐Catalyzed Decarboxylative Benzylation of α‐Cyano Aliphatic Carboxylate Salts

AbstractThe palladium‐catalyzed decarboxylative benzylation of α‐cyano aliphatic carboxylate salts with benzyl electrophiles was discovered. This reaction exhibits good functional group compatibility and proceeds under relatively mild conditions. A diverse range of quaternary, tertiary and secondary β‐aryl nitriles can be conveniently prepared by this method.

Palladium-Catalyzed, Asymmetric Mizoroki–Heck Reaction of Benzylic Electrophiles Using Phosphoramidites as Chiral Ligands

We report herein the first examples of asymmetric Mizoroki-Heck reactions using benzyl electrophiles. A new phosphoramidite was identified to be an effective chiral ligand in the palladium-catalyzed reaction. The reaction is compatible with polar functional groups and can be readily scaled up. Several cyclic olefins worked well as olefin components. Thirty-one examples are included.

Benzylic Phosphates as Electrophiles in the Palladium-Catalyzed Asymmetric Benzylation of Azlactones

Palladium-catalyzed asymmetric benzylation has been demonstrated with azlactones as prochiral nucleophiles in the presence of chiral bisphosphine ligands. Benzylic electrophiles are utilized under two sets of reaction conditions to construct a new tetrasubstituted stereocenter. Electron density of the phenyl ring dictates the reaction conditions, including the leaving group. The reported methodology represents a novel asymmetric carbon-carbon bond formation in an amino acid precursor.

Lewis base-promoted carbon–carbon sp3–sp3 coupling reactions of α-silyl silylethers

A Lewis base-promoted addition of α-silyl silylethers to primary halides has been developed. This new carbon–carbon sp3–sp3 bond-forming process accesses an unconventional reactivity pattern (d1 synthon) from easily accessible precursors. The strategy accommodates a variety of primary alkyl, allylic and benzylic electrophiles and α-silyl silylethers. These d1 synthons have also been used in the synthesis of cross pinacol and benzil products. Mechanistic studies indicate significant intermolecular silyl group exchange during the reaction.

Nitrates and NO-NSAIDs in cancer chemoprevention and therapy: In vitro evidence querying the NO donor functionality

Properties of the NO-ASA family of NO-donating NSAIDs (NO-NSAIDs), notably NCX 4016 ( mNO-ASA) and NCX 4040 ( pNO-ASA), reported in more than one hundred publications, have included positive preclinical data in cancer chemoprevention and therapy. Evidence is presented that the antiproliferative, the chemopreventive (antioxidant/electrophile response element (ARE) activation), and the anti-inflammatory activity of NO-ASA in cell cultures is replicated by X-ASA derivatives that are incapable of acting as NO donors. pBr-ASA and mBr-ASA are conisogenic with NO-ASA, but are not NO donors. The biological activity of pNO-ASA is replicated by pBr-ASA; and both pNO-ASA and pBr-ASA are bioactivated to the same quinone methide electrophile. The biological activity of mNO-ASA is replicated by mBr-ASA; mNO-ASA and mBr-ASA are bioactivated to different benzyl electrophiles. The observed activity is likely initiated by trapping of thiol biomolecules by the quinone and benzyl electrophiles, leading to depletion of GSH and modification of Cys-containing sensor proteins. Whereas all NO-NSAIDs containing the same structural “linker” as NCX 4040 and NCX 4016 are anticipated to possess activity resulting from bioactivation to electrophilic metabolites, this expectation does not extend to other linker structures. Nitrates require metabolic bioactivation to liberate NO bioactivity, which is often poorly replicated in vitro, and NO bioactivity provided by NO-NSAIDs in vivo provides proven therapeutic benefits in mitigation of NSAID gastrotoxicity. The in vivo properties of X-ASA drugs await discovery.

Phase-Transfer-Catalyzed Asymmetric Acylimidazole Alkylation

2-Acylimidazoles are alkylated under phase-transfer conditions with cinchonidinium catalysts at -40 degrees C with allyl and benzyl electrophiles in high yield with excellent enantioselectivity (79 to >99% ee). The acylimidazole substrates are made in three steps from bromoacetic acid via the N-acylmorpholine adduct. The catalyst is made in high purity allowing for S-product formation (6-20 h) under mild conditions, consistent with an ion-pair mechanism. The products are readily converted to useful ester products using methyltriflate and sodium methoxide, via a dimethylacylimidazolium intermediate without racemization. The process is efficient, direct, and amenable to other electrophiles and transformations that proceed through an enolate intermediate.

Palladium-catalyzed cross-coupling reaction of alkynylzincs with benzylic electrophiles

The reaction of alkynylzinc bromides with benzyl bromides or chlorides in the presence of a catalytic amount of Pd(DPEphos)Cl 2 in THF at 23 °C cleanly produces the corresponding benzylated alkynes in 73–97% yields. With 10 −3 mol % of Pd(DPEphos)Cl 2, the maximum turnover number of 7.1 × 10 4 has been observed for the formation of PhC CCH 2Ph.

Synthesis of phosphonium salts under microwave activation — Leaving group and phosphine substituents effects

The specific nonpurely thermal effects of microwaves were evidenced according to neutral or charged leaving groups during nucleophilic substitution of benzylic electrophiles with triphenylphosphine and tributylphosphine. Microwave (MW) irradiation considerably enhanced the reactions with charged alkylating agents, especially under solvent-free conditions. Results are interpreted considering the magnitude of MW effects according to the position of the transition state along the reaction coordinates.Key words: microwave irradiation, specific effects, phosphonium salts, leaving group effects.

Direct synthesis of H-aryl and H-heteroarylphosphinic esters via palladium-catalyzed cross-coupling of alkylphosphinates

Aryl, heteroaryl, and benzylic electrophiles can be coupled to in situ-generated alkylphosphinates (ROP(O)H 2) in moderate to good yields using palladium catalysis. For the first time, electrophiles other than simple aryl iodides can be employed in an experimentally straightforward, one-pot reaction. The direct formation of H-phosphinic esters avoids the separate esterification of H-phosphinic (phosphonous) acids and is particularly useful in the case of nitrogen-containing heteroaromatics. The reaction significantly expands the scope of related palladium-catalyzed phosphorus-carbon bond-forming reactions. To cite this article: Z. Huang et al., C. R. Chimie 7 (2004).

ChemInform Abstract: N‐ and O‐Alkylation of Isoquinolin‐1‐ones in the Mitsunobu Reaction: Development of Potential Drug Delivery Systems.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Solvolysis of substituted benzyl azoxyarenesulfonates:The IUPAC name for benzyl azoxyarenesulfonate is N-benzyl-N′-arylsulfonyloxydiazene N-oxide. characterisation of the transition state and the selectivity of benzylic intermediates in 50% aqueous 2,2,2-trifluoroethanolElectronic supplementary information (ESI) available: synthesis and analytical data of azoxyarenesulfonates. See http://www.rsc.org/suppdata/p2/b1/b106887n

Thirteen substituted benzyl azoxyarenesulfonates have been prepared and rate constants for solvolysis of twelve have been measured in 50% (v/v) aqueous 2,2,2-trifluoroethanol over a range of temperatures from which activation parameters and rate constants at 25 °C have been determined. A six-point Hammett correlation for substituents in the benzylic electrofuge, with azoxytoluene-p-sulfonate as the common nucleofuge, gives ρ(σ+) = −3.27. With 4-methylbenzyl as a common electrofuge, four substituents in the azoxybenzenesulfonate nucleofuge give ρ(σ) = 1.07. Comparison with model reactions indicates a synchronous concerted rate-limiting fragmentation for these substrates. With the less reactive 3-chlorobenzyl as electrofuge, ρ for substituents in the nucleofuge is only ca. 0.7 which indicates a lower degree of charge development in the arenesulfonate in the transition state for these reactions. Product analyses have been carried out for compounds of high, intermediate, and low reactivity. These indicate a reactivity–selectivity relationship for capture of the substituted benzylic electrophiles by water and 2,2,2-trifluoroethanol. Substituted benzaldehydes are formed from the less reactive substrates, indicating trapping of the first-formed benzylic carbenium ion by nitrous oxide and subsequent elimination of nitrogen and a proton; but yields are low and decrease as the substituted benzyl cation becomes increasingly stable.