Phosphoramidates as Steering Elements for Highly Selective Access to Complementary Imidazo[1,2-a]pyrimidine Isomers.

We report that selective N-phosphorylation of aminoimidazoles results in a key steering element that controls isomeric selectivity in the condensation of ß-ethoxy acrylamides and aminoimidazoles to furnish imidazo[1,2-a]pyrimidines. We identified conditions that provide highly selective (99:1) phosphorylation at the endo- or exocyclic nitrogen. Either the 2-amino or 4-amino isomer of the (benzo)imidazo[1,2-a]pyrimidine products could be isolated in 64-95% yield. Mass spectrometric analysis and computational studies give insight into the mechanism of this exceptionally selective transformation.

Palladium-catalyzed picolinamide-directed iodination of remote ortho-C-H bonds of arenes: Synthesis of tetrahydroquinolines.

A new palladium-catalyzed picolinamide (PA)-directed ortho-iodination reaction of ε-C(sp(2))-H bonds of γ-arylpropylamine substrates is reported. This reaction proceeds selectively with a variety of γ-arylpropylamines bearing strongly electron-donating or withdrawing substituents, complementing our previously reported PA-directed electrophilic aromatic substitution approach to this transformation. As demonstrated herein, a three step sequence of Pd-catalyzed γ-C(sp(3))-H arylation, Pd-catalyzed ε-C(sp(2))-H iodination, and Cu-catalyzed C-N cyclization enables a streamlined synthesis of tetrahydroquinolines bearing diverse substitution patterns.

Syntheses and Transformations of α-Amino Acids via Palladium-Catalyzed Auxiliary-Directed sp(3) C-H Functionalization.

α-Amino acids (αAA) are one of the most useful chiral building blocks for synthesis. There are numerous general strategies that have commonly been used for αAA synthesis, many of which employ de novo synthesis focused on enantioselective bond construction around the Cα center and others that consider conversion of existing αAA precursors carrying suitable functional groups on side chains (e.g., serine and aspartic acid). Despite significant advances in synthetic methodology, the efficient synthesis of enantiopure αAAs carrying complex side chains, as seen in numerous peptide natural products, remains challenging. Complementary to these "conventional" strategies, a strategy based on the selective functionalization of side chain C-H bonds, particularly sp(3) hybridized C-H bonds, of various readily available αAA precursors may provide a more straightforward and broadly applicable means for the synthesis and transformation of αAAs. However, many hurdles related to the low reactivity of C(sp(3))-H bonds and the difficulty of controlling selectivity must be overcome to realize the potential of C-H functionalization chemistry in this synthetic application. Over the past few years, we have carried out a systematic investigation of palladium-catalyzed bidentate auxiliary-directed C-H functionalization reactions for αAA substrates. Our strategies utilize two different types of amide-linked auxiliary groups, attached at the N or C terminus of αAA substrates, to exert complementary regio- and stereocontrol on C-H functionalization reactions through palladacycle intermediates. A variety of αAA precursors can undergo multiple modes of C(sp(3))-H functionalization, including arylation, alkenylation, alkynylation, alkylation, alkoxylation, and intramolecular aminations, at the ß, γ, and even δ positions to form new αAA products with diverse structures. In addition to transforming αAAs at previously unreachable positions, these palladium-catalyzed C-H functionalization strategies enable new retrosynthetic logic for the synthesis of many basic αAAs from a common alanine precursor. This approach reduces the synthetic difficulty for many αAAs by bypassing the requirement for stereocontrol at Cα and relies on straightforward and convergent single-bond coupling transformations at the ß-methyl position of alanine to access a wide range of ß-monosubstituted αAAs. Moreover, these ß-monosubstituted αAAs can undergo further C-H functionalization at the ß-methylene position to generate various ß-branched αAAs in a stereoselective and programmable fashion. These new strategies offer readily applicable methods for synthesis of challenging αAAs and may facilitate the efficient total synthesis of complex peptide natural products.

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.

Total synthesis of hibispeptin A via Pd-catalyzed C(sp3)-H arylation with sterically hindered aryl iodides.

To access the key Ile-Hpa pseudodipeptide motif in hibispeptins, a series of bidentate carboxamide-based auxiliary groups have been explored to facilitate the palladium-catalyzed arylation of unactivated γ-C(sp(3))-H bonds of Ile precursor with aryl iodides. A new pyridylmethylamine-based auxiliary group PR is introduced, which permits the use of more sterically hindered ortho-substituted aryl iodide substrates and can be removed under mild conditions. Pd-catalyzed PR-directed γ-C(sp(3))-H arylation enabled the first total synthesis of hibispeptin A.

Palladium-catalyzed stereoretentive olefination of unactivated C(sp3)-H bonds with vinyl iodides at room temperature: synthesis of ß-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 ß-vinyl α-amino acid products in a streamlined and controllable fashion, beginning from simple precursors.

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.

Use of a readily removable auxiliary group for the synthesis of pyrrolidones by the palladium-catalyzed intramolecular amination of unactivated γ C(sp(3))-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 ß-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.

Stereoselective synthesis of ß-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 ß-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.

Iodination of remote ortho-C-H bonds of arenes via directed S(E)Ar: a streamlined synthesis of tetrahydroquinolines.

A new strategy for the synthesis of tetrahydroquinolines (THQs) via the sequential functionalizations of remote C-H bonds is reported. This method uses a single picolinamide directing/protecting group to effect Pd-catalyzed γ-C(sp(3))-H arylation, metal-free ε-C(sp(2))-H iodination, and Cu-catalyzed intramolecular C-N cross-coupling. The overall sequence is efficient and versatile, and offers a streamlined synthesis of THQs with complex substitution patterns from readily available aryl iodide and aliphatic amine precursors.

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.

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.

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 ß-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.

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.