William A. Nack

Palladium-Catalyzed Picolinamide-Directed Alkylation of Unactivated C(sp3)–H Bonds with Alkyl Iodides

We report an efficient method for the alkylation of γ-C(sp(3))-H bonds of picolinamide-protected aliphatic amine substrates with primary alkyl iodides via palladium catalysis. Ag(2)CO(3) and dibenzyl phosphate, (BnO)(2)PO(2)H, are critical promoters of this reaction. These reactions provide a convenient and straightforward method for the preparation of high-value N-containing products from readily available amine and alkyl iodide precursors.

Efficient Alkyl Ether Synthesis via Palladium-Catalyzed, Picolinamide-Directed Alkoxylation of Unactivated C(sp3)–H and C(sp2)–H Bonds at Remote Positions

We report the efficient synthesis of alkyl ethers by the functionalization of unactivated sp(3)- and sp(2)-hybridized C-H bonds. In the Pd(OAc)(2)-catalyzed, PhI(OAc)(2)-mediated reaction system, picolinamide-protected amine substrates undergo facile alkoxylation at the γ or δ positions with a range of alcohols, including t-BuOH, to give alkoxylated products. This method features a relatively broad substrate scope for amines and alcohols, inexpensive reagents, and convenient operating conditions. This method highlights the emerging value of unactivated C-H bonds, particularly the C(sp(3))-H bond of methyl groups, as functional groups in organic synthesis.

Stereoselective Synthesis of β-Alkylated α-Amino Acids via Palladium-Catalyzed Alkylation of Unactivated Methylene C(sp3)–H Bonds with Primary Alkyl Halides

We report a new set of reactions based on the Pd-catalyzed alkylation of methylene C(sp(3))-H bonds of aliphatic quinolyl carboxamides with α-haloacetate and methyl iodide and applications in the stereoselective synthesis of various β-alkylated α-amino acids. These reactions represent the first generally applicable method for the catalytic alkylation of unconstrained and unactivated methylene C-H bonds with high synthetic relevance. When applied with simple isotope-enriched reagents, they also provide a convenient and powerful means to site-selectively incorporate isotopes into the carbon scaffolds of amino acid compounds.

Use of a Readily Removable Auxiliary Group for the Synthesis of Pyrrolidones by the Palladium‐Catalyzed Intramolecular Amination of Unactivated γ C(sp3)H Bonds

Easy on, easy off: Directing groups found to promote the palladium-catalyzed amination of γ C(sp(3) )H and C(sp(2) )H bonds of secondary amides included 5-methoxy-8-aminoquinoline, which can be removed under mild conditions (see scheme; CAN=ceric ammonium nitrate). In conjunction with a β-CH methylation or γ-CH arylation step, the γ-C(sp(3) )H amination provided access to complex pyrrolidones from readily available precursors.

Improved Protocol for Indoline Synthesis via Palladium-Catalyzed Intramolecular C(sp2)–H Amination

An efficient method has been developed for the synthesis of indoline compounds from picolinamide (PA)-protected β-arylethylamine substrates via palladium-catalyzed intramolecular amination of ortho-C(sp(2))-H bonds. These reactions feature high efficiency, low catalyst loadings, mild operating conditions, and the use of inexpensive reagents.

Copper-Catalyzed Carboxamide-Directed Ortho Amination of Anilines with Alkylamines at Room Temperature

In this report, a highly efficient method for the room temperature installation of alkyl amino motifs onto the ortho position of anilines via Cu-catalyzed carboxamide-directed amination with alkylamines is described. This method offers a practical solution for the rapid synthesis of complex arylamines from simple starting materials and enables new planning strategies for the construction of arylamine-containing pharmacophores. A single electron transfer (SET)-mediated mechanism is proposed.

Pd-catalyzed monoselective ortho-C-H alkylation of N-quinolyl benzamides: evidence for stereoretentive coupling of secondary alkyl iodides.

We report a method for the monoselective alkylation of ortho-C-H bonds of N-quinolyl benzamides with both primary and secondary alkyl halides under palladium catalysis. With promotion by NaHCO3 and (BnO)2PO2H or (PhO)2PO2H, symmetric benzamide substrates can be selectively ortho-alkylated to give either mono- or dialkylated products by simply adjusting the amount of NaHCO3 applied. The use of phosphate notably improves the alkylation yield, although it may not be directly involved in C-H palladation or the subsequent functionalization step. Kinetic isotope effect studies indicate that C-H palladation is not the rate-limiting step. Examination of the reactions of an isolated palladacycle intermediate with both cis- and trans-4-methylcyclohexyl iodides revealed surprising stereoretentive couplings of these alkyl iodides. This evidence strongly suggests that the functionalization of the palladacycle with secondary alkyl iodides proceeds via a rarely precedented concerted oxidative addition pathway.

Palladium-catalyzed trifluoroacetate-promoted mono-arylation of the β-methyl group of alanine at room temperature: synthesis of β-arylated α-amino acids through sequential C–H functionalization

We report a highly efficient and practical protocol for palladium-catalyzed N-quinolylcarboxamide (AQ)-directed arylation of the unactivated β-C(sp3)–H bonds of alanine with aryl iodides at room temperature. For the first time, a broad range of easily accessible aryl iodides can be installed onto the β-methyl group of AQ-coupled phthaloyl alanine mono-selectively, providing both natural and unnatural aromatic α-amino acids. Access to these mono-arylated compounds enables subsequent AQ-directed diastereoselective C–H functionalization, allowing the preparation of various β-disubstituted aromatic α-amino acids in a programmable manner.

Palladium-Catalyzed Alkenylation and Alkynylation of ortho-C(sp2)–H Bonds of Benzylamine Picolinamides

An efficient functionalization of ortho-C(sp(2))-H bonds of picolinamide (PA)-protected benzylamine substrates with a range of vinyl iodides as well as acetylenic bromide is reported. ortho-Phenyl benzoic acid (oPBA) acts as an effective promoter in this reaction system. This method provides a practical strategy to access highly functionalized benzylamine compounds for organic synthesis.

Palladium-catalyzed stereoretentive olefination of unactivated C(sp3)-H bonds with vinyl iodides at room temperature: synthesis of β-vinyl α-amino acids.

A method is reported for palladium-catalyzed N-quinolyl carboxamide-directed olefination of the unactivated C(sp(3))-H bonds of phthaloyl alanine with a broad range of vinyl iodides at room temperature. This reaction represents the first example of the stereoretentive installation of multisubstituted terminal and internal olefins onto unactivated C(sp(3))-H bonds. These methods enable access to a wide range of challenging β-vinyl α-amino acid products in a streamlined and controllable fashion, beginning from simple precursors.