Reductive C2‐Alkylation of Pyridine and Quinoline N‐Oxides Using Wittig Reagents

The ability to alkylate pyridines and quinolines is important for their further development as pharmaceuticals and agrochemicals, and for other purposes. Herein we describe the unprecedented reductive alkylation of pyridine and quinoline N‐oxides using Wittig reagents. A wide range of pyridine and quinoline N‐oxides were converted into C2‐alkylated pyridines and quinolines with excellent site selectivity and functional‐group compatibility. Sequential C?H functionalization reactions of pyridine and quinoline N‐oxides highlight the utility of the developed method. Detailed labeling experiments were performed to elucidate the mechanism of this process.     

Cu‐Catalyzed Asymmetric Allylic Alkylation of Phosphonates and Phosphine Oxides with Grignard Reagents

An efficient and highly enantioselective copper‐catalyzed allylic alkylation of phosphonates and phosphine oxides with Grignard reagents and Taniaphos or phosphoramidites as chiral ligands is reported. Transformation of these products leads to a variety of new phosphorus‐containing chiral intermediates.     

C‐Selective and Diastereoselective Alkyl Addition to β,γ‐Alkynyl‐α‐imino Esters with Zinc(II)ate Complexes

Since umpolung α‐imino esters contain three electrophilic centers, regioselective alkyl addition with traditional organometallic reagents has been a serious problem in the practical synthesis of versatile chiral α‐amino acid derivatives. An unusual C‐alkyl addition to α‐imino esters using a Grignard reagent (RMgX)‐derived zinc(II)ate was developed. Zinc(II)ate complexes consist of a Lewis acidic [MgX]⁺ moiety, a nucleophilic [R₃Zn]^? moiety, and 2 [MgX₂]. Therefore, the ionically separated [R₃Zn]^? selectively attacks the imino carbon atom ,which is most strongly activated by chelation of [MgX]⁺. In particular, chiral β,γ‐alkynyl‐α‐imino esters can strongly promote highly regio‐ and diastereoselective C‐alkylation because of structural considerations, and the corresponding optically active α‐quaternary amino acid derivatives are obtained within 5 minutes in high to excellent yields.     

Nanosized Iron- or Copper-Catalyzed Homocoupling of Aryl,Heteroaryl, Benzyl,and Alkenyl Grignard Reagents

Under very mild reaction conditions, iron or copper nanoparticles efficiently promoted the homocoupling of different Grignard reagents in tetrahydrofuran at room temperature. The nanosized iron or copper particles were generated in situ in a simple and economical way from commercially available FeCl₂ or CuCl₂, respectively, an excess of lithium powder, and a catalytic amount (5 mol%) of 4,4′-di-tert-butylbiphenyl (DTBB) as electron carrier. The reaction of a series of aryl, heteroaryl, benzyl, and alkenyl Grignard reagents in the presence of a substoichiometric amount of the iron or copper nanoparticles led to the formation of the corresponding homocoupling products in good yield.     

Nickel‐Catalyzed Dimerization and Alkylarylation of 1,3‐Dienes with Alkyl Fluorides and Aryl Grignard Reagents

In the presence of a nickel catalyst, 1,3‐butadiene undergoes selective dimerization and alkylarylation with alkyl fluorides and aryl Grignard reagents to give 1,6‐octadienes with alkyl and aryl groups at the 3‐ and 8‐positions, respectively, by the consecutive formation of three carbon–carbon bonds. The formation of an anionic nickel complex plays an important role in forming C?C bonds with alkyl fluorides.     

Copper‐Free Asymmetric Allylic Alkylation with a Grignard Reagent: Design of the Ligand and Mechanistic Studies

The Cu‐free asymmetric allylic alkylation, catalysed by NHC, with Grignard reagents is reported on allyl bromide derivatives with good results. The enantioselectivity was quite homogeneous (around 85 % ee) on large and various substrates, regardless of the nature of the Grignard reagent. The formation of stereogenic quaternary centres was highly regioselective for both aliphatic and aromatic derivatives with good enantiomeric excess (up to 92 % ee). The methodology developed was found to be complementary with the Cu‐catalysed version. Several new NHCs were tested with improved efficiency. In addition, mechanistic studies, using NMR spectroscopy, led to the discovery of the catalytically active species.     

Catalytic Reactions of Titanium Alkoxides with Grignard Reagents and Imines: A Mechanistic Study

The reactivity of Grignard reagents towards imines in the presence of catalytic and stoichiometric amounts of titanium alkoxides is reported. Alkylation, reduction, and coupling of imines take place. Whereas reductive coupling is the major reaction in stoichiometric reactions, alkylation is favored in catalytic reactions. Mechanistic studies clearly indicate that intermediates involved in the two reactions are different. Catalytic reactions involve a metal–alkyl complex. This has been confirmed by reactions of deuterium‐labeled substrates and different alkylating agents. Under the stoichiometric conditions, however, titanium olefin complexes are formed through reductive elimination, probably through a multinuclear intermediate.     

Copper-Catalyzed Addition of Grignard Reagents to in situ Generated Indole-Derived Vinylogous Imines

Chiral indole derivatives are ubiquitous motifs in pharmaceuticals and alkaloids. Herein, the first protocol for catalytic asymmetric conjugate addition of Grignard reagents to various sulfonyl indoles, offering a straightforward approach for the synthesis of chiral 3-sec-alkyl-substituted indoles in high yields and enantiomeric ratios is presented. This methodology makes use of a chiral catalyst based on copper phosphoramidite complexes and in situ formation of vinylogous imine intermediates.     

Transition‐Metal‐Free Regioselective Alkylation of Pyridine N‐Oxides Using 1,1‐Diborylalkanes as Alkylating Reagents

Reported herein is an unprecedented base‐promoted deborylative alkylation of pyridine N‐oxides using 1,1‐diborylalkanes as alkyl sources. The reaction proceeds efficiently for a wide range of pyridine N‐oxides and 1,1‐diborylalkanes with excellent regioselectivity. The utility of the developed method is demonstrated by the sequential C?H arylation and methylation of pyridine N‐oxides. The reaction also can be applied for the direct introduction of a methyl group to 9‐O‐methylquinine N‐oxide, thus it can serve as a powerful method for late‐stage functionalization.     

Synthesis of Osthole Derivatives with Grignard Reagents and Their Larvicidal Activities on Mosquitoes

The structure of osthole has been modified to improve its larvicidal activity against mosquitoes. A new efficient synthesis of osthole derivatives with Grignard reagents has been developed, which employs CuI and LiCl as promoters and covers a broad range of substrates to afford the corresponding products in mild to good yields (up to 83%). Bio‐activity evaluation showed that several products exhibited better activities than osthole.     

Iron‐catalyzed Cross‐Coupling of Propargyl Carboxylates and Grignard Reagents: Synthesis of Substituted Allenes

Presented herein is a mild, facile, and efficient iron‐catalyzed synthesis of substituted allenes from propargyl carboxylates and Grignard reagents. Only 1–5 mol % of the inexpensive and environmentally benign [Fe(acac)₃] at ?20 °C was sufficient to afford a broad range of substituted allenes in excellent yields. The method tolerates a variety of functional groups.     

Pd‐NHC‐Catalyzed Alkynylation of General Aryl Sulfides with Alkynyl Grignard Reagents

Cross‐coupling reactions of unactivated aryl sulfides with alkynylmagnesium chloride have been invented to afford 1‐aryl‐1‐alkynes with the aid of a palladium/N‐heterocyclic carbene complex. This reaction has by far the widest scope of all transformations utilizing aryl sulfides and alkynes, while known cross‐coupling alkynylations of aryl‐sulfur electrophiles require activated azaaryl sulfides, thiolactams, or arenesulfonyl chlorides. The alkynylation of aryl sulfides is compatible with typical protecting functional groups. The alkynylation is applied to the synthesis of benzofuran‐based fluorescent molecules by taking advantage of characteristic organosulfur chemistry.