Recent Advances in the Nickel-Catalyzed Alkylation of C-H Bonds.

Functionalization of C-H bonds has emerged as a powerful strategy for converting inert, nonfunctional C-H bonds into their reactive counterparts. A wide range of C-H bond functionalization reactions has become possible by the catalysis of metals, typically from the second row of transition metals. First-row transition metals can also catalyze C-H functionalization, and they have the merits of greater earth-abundance, lower cost and better environmental friendliness in comparison to their second-row counterparts. C-H bond alkylation is a particularly important C-H functionalization reaction due to its chemical significance and its applications in natural product synthesis. This review covers Ni-catalyzed C-H bond alkylation reactions using alkyl halides and olefins as alkyl sources.

Catalytic Photoredox C-H Arylation of 4-Oxo-4H-pyrido[1,2-a]pyrimidine-3-diazonium Tetrafluoroborates and Related Heteroaryl Diazonium Salts.

Irradiation of mixtures of title diazonium salts and heteroarenes with green light (510 nm) in the presence of eosin Y disodium salt (EY-Na2) as a photocatalyst furnished the corresponding arylation products in 8-63% yields. The proposed photocatalytic cycle is analogous to that proposed previously for closely related photoredox C-H arylations with aryl diazonium salts as aryl radical sources. This method has a broad substrate scope and represents a metal-free alternative for the synthesis of 3-heteroaryl-substituted 4H-quinolizin-4-ones and azino- and azolo-fused pyrimidones with a bridgehead nitrogen atom.

Synthesis and Catalytic Activity of Bifunctional Phase-Transfer Organocatalysts Based on Camphor.

Ten novel bifunctional quaternary ammonium salt phase-transfer organocatalysts were synthesized in four steps from (+)-camphor-derived 1,3-diamines. These quaternary ammonium salts contained either (thio)urea or squaramide hydrogen bond donor groups in combination with either trifluoroacetate or iodide as the counteranion. Their organocatalytic activity was evaluated in electrophilic heterofunctionalizations of ß-keto esters and in the Michael addition of a glycine Schiff base with methyl acrylate. α-Fluorination and chlorination of ß-keto esters proceeded with full conversion and low enantioselectivities (up to 29% ee). Similarly, the Michael addition of a glycine Schiff base with methyl acrylate proceeded with full conversion and up to 11% ee. The new catalysts have been fully characterized; the stereochemistry at the C-2 chiral center was unambiguously determined.

Synthesis of Six-Membered N-Heterocyclic Carbene Precursors Based on Camphor.

The endo- and exo-N-heterocyclic carbene precursors based on camphor were prepared diastereoselectively in five synthetic steps starting from (1S)-(+)-ketopinic acid. The obtained N-heterocyclic carbene precursors were investigated in an asymmetric benzoin reaction. All new compounds were fully characterized, and the absolute configurations were determined via X-ray diffraction and NOESY measurements.

Regioselective Synthesis of 5- and 3-Hydroxy-N-Aryl-1H-Pyrazole-4-Carboxylates and Their Evaluation as Inhibitors of Plasmodium falciparum Dihydroorotate Dehydrogenase.

In silico evaluation of various regioisomeric 5- and 3-hydroxy-substituted alkyl 1-aryl-1H-pyrazole-4-carboxylates and their acyclic precursors yielded promising results with respect to their binding in the active site of dihydroorotate dehydrogenase of Plasmodium falciparum (PfDHODH). Consequently, four ethyl 1-aryl-5-hydroxy-1H-pyrazole-4-carboxylates and their 3-hydroxy regioisomers were prepared by two-step syntheses via enaminone-type reagents or key intermediates. The synthesis of 5-hydroxy-1H-pyrazoles was carried out using the literature protocol comprising acid-catalyzed transamination of diethyl [(dimethylamino)methylene]malonate with arylhydrazines followed by base-catalyzed cyclization of the intermediate hydrazones. For the synthesis of isomeric methyl 1-aryl-3-hydroxy-1H-pyrazole-4-carboxylates, a novel two-step synthesis was developed. It comprises acylation of hydrazines with methyl malonyl chloride followed by cyclization of the hydrazines with tert-butoxy-bis(dimethylamino)methane. Testing the pyrazole derivatives for the inhibition of PfDHODH showed that 1-(naphthalene-2-yl)-5-hydroxy-1H-pyrazole-4-carboxylate and 1-(naphthalene-2-yl)-, 1-(2,4,6-trichlorophenyl)-, and 1-[4-(trifluoromethyl)phenyl]-3-hydroxy-1H-pyrazole-4-carboxylates (~30% inhibition) were slightly more potent than a known inhibitor, diethyl α-{[(1H-indazol-5-yl)amino]methylidene}malonate (19% inhibition).

Regioselective Ru(II)/Pd(0) Dual Catalysis: One-Pot C-H Diarylation of Five-Membered Heterocyclic Derivatives.

Herein, we report a one-pot site-selective dual metal catalyzed C-H diarylation reaction for the synthesis of multiarylated thiophene and furan derivatives in yields up to 92%. The regioselectivity of the developed methodology was achieved with the sequential use of two metal catalysts within a single vessel, starting with a Ru(II)-catalyzed C3 arylation assisted by an azine directing group, followed by a Pd(0)-catalyzed C-H functionalization on the C5-position of the five-membered heterocycle. Furthermore, the kinetic studies support that the position of the nitrogen atom within the azine moiety exhibits an evident effect on the efficiency of the ruthenium-catalyzed arylation step.

Synthesis of 6,7-Dihydro-1H,5H-pyrazolo[1,2-a]pyrazoles by Azomethine Imine-Alkyne Cycloadditions Using Immobilized Cu(II)-Catalysts.

A series of 12 silica gel-bound enaminones and their Cu(II) complexes were prepared and tested for their suitability as heterogeneous catalysts in azomethine imine-alkyne cycloadditions (CuAIAC). Immobilized Cu(II)-enaminone complexes showed promising catalytic activity in the CuAIAC reaction, but these new catalysts suffered from poor reusability. This was not due to the decoordination of copper ions, as the use of enaminone ligands with additional complexation sites resulted in negligible improvement. On the other hand, reusability was improved by the use of 4-aminobenzoic acid linker, attached to 3-aminopropyl silica gel via an amide bond to the enaminone over the more hydrolytically stable N-arylenamine C-N bond. The study showed that silica gel-bound Cu(II)-enaminone complexes are readily available and suitable heterogeneous catalysts for the synthesis of 6,7-dihydro-1H,5H-pyrazolo[1,2-a]pyrazoles.

Self-Assembly of Multinuclear Sandwich Silver(I) Complexes by Cooperation of Hexakis(azaheteroaryl)benzene Ligands, Argentophilic Interactions, and Fluoride Inclusion.

Self-assembly of AgOTf and AgF with the hexatopic ligands hexakis(pyridin-2-yl)benzene (2) and 2,4,6-tris(pyridin-2-yl)-1,3,5-tris(quinolin-2-yl)benzene (3) affords the discrete sandwich-shaped complexes [Ag4F(2)2](OTf)3, [Ag4F(3)2](OTf)3, and [Ag5F(2)2](OTf)4. The solid-state structures of the complexes were characterized by single-crystal X-ray diffraction analysis, which revealed that the fluoride anion is coordinated in the center of the Ag4-square or Ag5-pentagon units which are positioned between two molecules of the hexakis(azaheteroaryl)benzene. The generation of complexes is dictated by a unique cooperation of ligand coordination, argentophilicity, and fluoride anion inclusion. All three complexes adopt highly symmetrical structures in solution, as evidenced by appearance of one set of proton resonances for the two ligands arranged face to face.

Stereodivergent Synthesis of Camphor-Derived Diamines and Their Application as Thiourea Organocatalysts.

A series of 18 regio- and stereo-chemically diverse chiral non-racemic 1,2-, 1,3-, and 1,4-diamines have been synthesized from commercial (1S)-(+)-ketopinic acid and (1S)-(+)-10-camphorsulfonic acid. The structures of the diamines are all based on the d-(+)-camphor scaffold and feature isomeric diversity in terms of regioisomeric attachment of the primary and the tertiary amine function and the exo/endo-isomerism. Diamines were transformed into the corresponding noncovalent bifunctional thiourea organocatalysts, which have been evaluated for catalytic activity in the conjugative addition of 1,3-dicarbonyl nucleophiles (dimethyl malonate, acetylacetone, and dibenzoylmethane) to trans-ß-nitrostyrene. The highest enantioselectivity was achieved in the reaction with acetylacetone as nucleophile using endo-1,3-diamine derived catalyst 52 (91.5:8.5 er). All new organocatalysts 48-63 have been fully characterized. The structures and the absolute configurations of eight intermediates and thiourea derivative 52 were also determined by X-ray diffraction.

Tetrahydro-1H,5H-pyrazolo[1,2-a]pyrazole-1-carboxylates as inhibitors of Plasmodium falciparum dihydroorotate dehydrogenase.

The reactions between 5-substituted pyrazolidine-3-ones, aldehydes, and methyl methacrylate provided tetrahydropyrazolo[1,2-a]pyrazole-1-carboxylates as mixtures of syn- and anti-diastereomers. Testing for inhibition of dihydroorotate dehydrogenase of Plasmodium falciparum (PfDHODH) revealed high activity of some anti-isomers of the methyl esters, while the corresponding carboxylic acids and carboxamides were not active. The most active representative, methyl (1S*,3S*,5R*)-1,5-dimethyl-7-oxo-3-phenyltetrahydro-1H,5H-pyrazolo[1,2-a]pyrazole-1-carboxylate (IC50 = 2.9 ±â€¯0.3 µM), also exhibited very high selectivity of the parasite enzyme vs. the human enzyme, PfDHODH/HsDHODH > 350. According to the molecular docking score, this high activity is explainable by synergic interactions of the methyl, phenyl and the CO2Me substituent with the hydrophobic pockets in the active site of the enzyme. The carboxylic acid and carboxamides derived from this compound did not inhibit PfDHODH.

Synthesis of Non-Racemic Pyrazolines and Pyrazolidines by [3+2] Cycloadditions of Azomethine Imines.

Asymmetric [3+2] cycloadditions of azomethine imines comprise a useful synthetic tool for the construction of pyrazole derivatives with a variable degree of saturation and up to three stereogenic centers. As analogues of pyrrolidines and imidazolidines that are abundant among natural products, pyrazoline and pyrazolidine derivatives represent attractive synthetic targets due to their extensive applications in the chemical and medicinal industries. Following the increased understanding of the mechanistic aspect of metal-catalyzed and organocatalyzed [3+2] cycloadditions of 1,3-dipoles gained over recent years, significant strides have been taken to design and develop new protocols that proceed efficiently under mild synthetic conditions and duly benefit from superior functional group tolerance and selectivity. In this review, we represent the current state of the art in this field and detailed methods for the synthesis of non-racemic pyrazolines and pyrazolidines via [3+2] metal and organocatalyzed transformations reported since the seminal work of Kobayashi et al. and Fu et al. in 2002 and 2003 up to the end of year 2017.

Synthesis and Reduction of 10-Phthalimidocamphor Oxime.

10-Phthalimidocamphor oxime was prepared from easily available 10-iodocamphor in two steps. Reduction of the oxime functionality resulted in the formation of two novel polycyclic isoindolinone heterocycles, the attempted preparation of the primary amine failed. The structures of novel heterocycles were unambiguously confirmed by single crystal X-ray diffraction as well as NMR techniques.

Synthesis of Novel 5-(N-Boc-N-Benzyl-2-aminoethyl)-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidin-3-carboxamides and Their Inhibition of Cathepsins B and K.

Eight novel 5-(N-Boc-N-benzyl-2-aminoethyl)-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidin-3-carboxamides were prepared in three steps from methyl 3-amino-1H-pyrazole-4-carboxylate and methyl 5-(benzyl(tert-butoxycarbonyl)amino)-3-oxopentanoate. The synthetic procedure comprises cyclocondensation of the above starting compounds, hydrolysis of the ester, and bis(pentafluorophenyl) carbonate (BPC)-mediated amidation. Title carboxamides were tested for inhibition of cathepsins K and B. The N-butylcarboxamide 5a exhibited appreciable inhibition of cathepsin K (IC50 ~ 25 µM), while the strongest inhibition of cathepsin B was achieved with N-(2-picolyl)carboxamide 5c (IC50 ~ 45 µM).

Asymmetric Bio- and Chemoreduction of 2-Benzylidenecyclopentanone Derivatives.

Highly efficient asymmetric reduction of 2-benzylidenecyclopentanone derivatives to give the respective exocyclic allylic alcohols in ee's up to 96% was performed with chiral oxazaborolidine-based catalysts. Complete enantioselectivity furnishing (S)-configured alcohol product could be achieved by bioreduction of 2-(4-chlorobenzylidene)cyclopentanone with Daucus carota root. The synthesized compounds may be used as enantiomerically enriched standards for the monitoring of the enzyme-catalyzed redox processes.

Synthesis of Novel 3D-Rich α-Amino Acid-Derived 3-Pyrazolidinones.

Synthetic approaches towards novel 3-pyrazolidinone derivatives functionalized at positions N(1) and/or C(5) were studied. 5-Aminoalkyl-3-pyrazolidinones were prepared in four steps from N-protected glycines via Masamune-Claisen homologation, reduction, O-mesylation, and cyclisation with a hydrazine derivative. The free amines were prepared by acidolytic deprotection. Title compound was also prepared by 'ring switching' transformation of N-Boc-pyrrolin-2(5H)-one with hydrazine hydrate. Hydrogenolytic deprotection of 5-(N-alkyl-N-Cbz-aminomethyl)pyrazolidine-3-ones followed by cyclisation with 1,1'-carbonyldiimidazole (CDI) gave two novel representatives of perhydroimidazo[1,5-b] pyrazole, which is an almost unexplored heterocyclic system. Amidation of 3-oxopyrazolidine-5-carboxylic acid gave the corresponding carboxamides in moderate yields. Diastereomeric non-racemic carboxamides obtained from (S)-AlaOMe and (S)-ProOMe were separated by MPLC.

"Click" Chemistry: Application of Copper Metal in Cu-Catalyzed Azomethine Imine-Alkyne Cycloadditions.

A series of 16 copper-catalyzed azomethine imine-alkyne cycloaddition (CuAIAC) reactions between four pyrazolidinone-1-azomethine imines and four terminal ynones gave the corresponding fluorescent cycloadducts as bimane analogues in very high yields. The applicability of CuAIAC was demonstrated by the fluorescent labeling of functionalized polystyrene and by using Cu-C and Cu-Fe as catalysts. Experimental evidence, kinetic measurements, and correlation between a clean catalyst surface and the reaction rate are in agreement with a homotopic catalytic system with catalytic Cu(I)-acetylide formed from Cu(0) by "in situ" oxidation. The availability of azomethine imines, mild reaction conditions, simple workup, and scalability make CuAIAC a viable supplement to the Cu-catalyzed azide-alkyne cycloaddition reaction in "click" chemistry.

Synthesis and Rotational Isomerism of 1-Substituted Methyl (S)-[5-(2-Nitrophenyl)-1H-pyrazole-4-carbonyl]alaninates.

Seven title compounds 12a-g and the (S)-prolinate analogue 13 were prepared in five steps from 2-nitrobenzoic acid (7). Reduction of the nitro group followed by derivatization of the so formed anilines 14 gave the N-alkyl-(15a-c), N-acyl-(16a,b and 19), and N-vinyl derivative 20. NMR spectra of (S)-alanine and (S)-proline derived compounds 12, 13, 14-16, 19, and 20 exhibited two sets of signals corresponding to pairs of conformational diastereomers. The free energy barriers of rotation, ΔG(‡)298 = 82-86 kJ mol(-1), were determined by (1)H NMR for 12a, 12d, 12f, and 12g and evaluated by DFT calculations.

Synthesis of 3D-Rich Heterocycles: Hexahydropyrazolo[1,5-a]pyridin-2(1H)-ones and Octahydro-2H-2a,2a1-diazacyclopenta[cd]inden-2-ones.

Two cyclic azomethine imines, 7-methyl- and 7-phenyl-2-oxo-Δ7-hexahydropyrazolo[1,5-a]pyridin-8-ium-1-ide, were prepared in seven steps from the respective commercially available δ-keto acids. The addition of Grignard reagents followed by N-alkylation at position 1 afforded the 1,7,7-trisubstituted hexahydropyrazolo[1,5-a]pyridin-2(1H)-ones, whereas 1,3-dipolar cycloadditions of these dipoles to typical acetylenic and olefinic dipolarophiles gave 4a-substituted 2a,2a1-diazacyclopenta[cd]indene derivatives as the first representatives of a novel heterocyclic system. Regio- and stereoselectivity as well as the mechanism of these [3 + 2]-cycloadditions were evaluated using computational and experimental methods. The data obtained were in agreement with the polar concerted cycloaddition mechanism via the energetically favorable syn/endo-transition states.

Absolute Configuration Determination of 2,3-Dihydro-1H,5H-pyrazolo[1,2-a]pyrazoles Using Chiroptical Methods at Different Wavelengths.

A correlation between the absolute configuration and chiroptical properties of nonracemic 1,6,7-trisubstituted 2,3-dihydro-1H,5H-pyrazolo[1,2-a]pyrazoles was studied. A series of 16 novel representatives were prepared by Cu-catalyzed [3 + 2] cycloadditions of racemic (Z)-2-benzylidene-5-oxopyrazolidin-2-ium-1-ides to tert-butyl (S)-(3-oxopent-4-yn-2-yl)carbamate, and their structures were determined by NMR, VCD, ECD, and X-ray diffraction. A clear correlation between the sign of specific rotation and configuration at position C(1) allows for easy determination of the absolute configuration of 1,6,7-trisubstituted 2,3-dihydro-1H,5H-pyrazolo[1,2-a]pyrazoles by ECD and NMR. While VCD, requiring milligram quantities, allowed the determination of the correct relative and absolute configuration without additional information from other methods, the stereochemical analysis by ECD required knowledge of the relative configuration derived from NMR at a comparable computational level.

Synthesis and preliminary biological evaluations of (+)-isocampholenic acid-derived amides.

The synthesis of two novel (+)-isocampholenic acid-derived amines has been realized starting from commercially available (1S)-(+)-10-camphorsulfonic acid. The novel amines as well as (+)-isocampholenic acid have been used as building blocks in the construction of a library of amides using various aliphatic, aromatic, and amino acid-derived coupling partners using BPC and CDI as activating agents. Amide derivatives have been assayed against several enzymes that hold potential for the development of new drugs to battle bacterial infections and Alzheimer's disease. Compounds 20c and 20e showed promising selective sub-micromolar inhibition of human butyrylcholinesterase [Formula: see text] ([Formula: see text] values [Formula: see text] and [Formula: see text], respectively).