Phosphorescent Cyclometalated Palladium(II) and Platinum(II) Complexes Derived from Diaminocarbene Precursors.

Metal-mediated self-assembly of isocyanides and methyl 4-aminopyrimidine-5-carboxylate leads to luminescent PdII and PtII complexes featuring C,N-cyclometalated acyclic diaminocarbene (ADC) ligands. The solid-state luminescent properties of these diaminocarbene derivatives are attributed to their triplet-state metal/metal-to-ligand charge-transfer (3MMLCT) nature, which is driven by attractive intermolecular M···M interactions further reinforced by the intramolecular π-π interactions even in the structure of the Pd compound, which is the first Pd-ADC phosphor reported.

Gold-Catalyzed Nitrene Transfer from Benzofuroxans to N-Allylynamides: Synthesis of 3-Azabicyclo[3.1.0]hexanes.

The gold-catalyzed reaction between benzofuroxans, functioning as nitrene transfer reagents, and N-allylynamides leads to 3-azabicyclo[3.1.0]hexan-2-imines. This highly selective annulation proceeds smoothly under mild conditions (5 mol % Ph3PAuNTf2, PhCl, 60 °C) and exhibits high functional group tolerance (21 examples, ≤96% yields). The obtained cyclopropanated products represent a useful synthetic platform with an easily modulated substitution pattern as illustrated by their postmodifications. Intramolecular cyclopropanation of gold α-imino carbene intermediates is suggested as a key step of the catalytic cycle.

Acid-catalyzed [2 + 2 + 2] cycloaddition of two cyanamides and one ynamide: highly regioselective synthesis of 2,4,6-triaminopyrimidines.

Triflic acid (10 mol%) catalyzes the highly regioselective [2 + 2 + 2] cycloaddition between two cyanamides and one ynamide to grant the 2,4,6-triaminopyrimidine core. The developed synthetic method is effective for the preparation of a family of the diversely substituted heterocyclic products (30 examples; yields up to 94%). The synthesis can be easily scaled up and conducted in gram quantities. As demonstrated by the post-functionalizations involving the amino-substituents, the obtained heterocycles represent a useful platform for the construction of miscellaneous pyrimidine-based frameworks. The performed density functional theory calculations verified a particular role of H+, functioning as an electrophilic activator, in the regioselectivity of the cycloaddition.

Hetero-Tetradehydro-Diels-Alder Cycloaddition of Enynamides and Cyanamides: Gold-Catalyzed Generation of Diversely Substituted 2,6-Diaminopyridines.

Gold(I)-catalyzed hetero-tetradehydro-Diels-Alder cycloaddition of enynamides and cyanamides comprises an efficient route to diversely substituted 2,6-diaminopyridines (28 examples; yields up to 99%). The reaction proceeds under very mild conditions (DCM, rt) with high functional group tolerance. The obtained 2,6-diaminopyridines represent a useful synthetic platform with an easily modulated substitution pattern for subsequent functionalizations of both the pyridine core and the N-substituents.

Oxygen Atom Transfer as Key To Reverse Regioselectivity in the Gold(I)-Catalyzed Generation of Aminooxazoles from Ynamides.

We report on gold(I)-catalyzed oxidative annulation involving ynamides, nitriles, and 2,3-dichloropyridine N-oxide. The application of 2,3-dichloropyridine N-oxide as an oxygen atom transfer reagent reverses the regioselectivity to give 5-amino-1,3-oxazoles, in comparison with the previously reported syntheses of aminooxazoles based on gold-catalyzed nitrene transfers to ynamides to furnish 4-amino-1,3-oxazoles. The developed oxygen atom transfer approach allows the generation of 1,3-oxazoles containing a variety of sulfonyl-protected alkylamino groups in the fifth position of the oxazole ring (29 examples; up to 88% yields). In addition, the use of N-substituted nitriles, namely cyanamides, leads to the facile generation of difficult-to-obtain 2,5-diaminooxazoles. The process is feasible for wide ranges of ynamides or nitriles, and it can be conducted in gram scale.

Comparative Study of the Steroidogenic Effects of Human Chorionic Gonadotropin and Thieno[2,3-D]pyrimidine-Based Allosteric Agonist of Luteinizing Hormone Receptor in Young Adult, Aging and Diabetic Male Rats.

Low-molecular-weight agonists of luteinizing hormone (LH)/human chorionic gonadotropin (hCG) receptor (LHCGR), which interact with LHCGR transmembrane allosteric site and, in comparison with gonadotropins, more selectively activate intracellular effectors, are currently being developed. Meanwhile, their effects on testicular steroidogenesis have not been studied. The purpose of this work is to perform a comparative study of the effects of 5-amino-N-tert-butyl-4-(3-(1-methylpyrazole-4-carboxamido)phenyl)-2-(methylthio)thieno[2,3-d] pyrimidine-6-carboxamide (TP4/2), a LHCGR allosteric agonist developed by us, and hCG on adenylyl cyclase activity in rat testicular membranes, testosterone levels, testicular steroidogenesis and spermatogenesis in young (four-month-old), aging (18-month-old) and diabetic male Wistar rats. Type 1 diabetes was caused by a single streptozotocin (50 mg/kg) injection. TP4/2 (20 mg/kg/day) and hCG (20 IU/rat/day) were administered for 5 days. TP4/2 was less effective in adenylyl cyclase stimulation and ability to activate steroidogenesis when administered once into rats. On the 3rd-5th day, TP4/2 and hCG steroidogenic effects in young adult, aging and diabetic rats were comparable. Unlike hCG, TP4/2 did not inhibit LHCGR gene expression and did not hyperstimulate the testicular steroidogenesis system, moderately increasing steroidogenic proteins gene expression and testosterone production. In aging and diabetic testes, TP4/2 improved spermatogenesis. Thus, during five-day administration, TP4/2 steadily stimulates testicular steroidogenesis, and can be used to prevent androgen deficiency in aging and diabetes.

Nature of the Nucleophilic Oxygenation Reagent Is Key to Acid-Free Gold-Catalyzed Conversion of Terminal and Internal Alkynes to 1,2-Dicarbonyls.

2,3-Dichloropyridine N-oxide, a novel oxygen transfer reagent, allows the conductance of the gold(I)-catalyzed oxidation of alkynes to 1,2-dicarbonyls in the absence of any acid additives and under mild conditions to furnish the target species, including those derivatized by highly acid-sensitive groups. The developed strategy is effective for a wide range of alkyne substrates such as terminal- and internal alkynes, ynamides, alkynyl ethers/thioethers, and even unsubstituted acetylene (40 examples; yields up to 99%). The oxidation was successfully integrated into the trapping of reactive dicarbonyls by one-pot heterocyclization and into the synthesis of six-membered azaheterocycles. This synthetic acid-free route was also successfully applied for the total synthesis of a natural 1,2-diketone.

Gold(I)-Catalyzed Oxidation of Acyl Acetylenes to Vicinal Tricarbonyls.

Efficient gold(I)-catalyzed oxidation of COR2-functionalized internal alkynes to vicinal tricarbonyl compounds by 2,6-dichloropyridine N-oxide proceeds under mild conditions (DCM, rt). This catalytic reaction provides a good to excellent yielding route to diverse tricarbonyls such as α,ß-diketoesters, 1,2,3-triketones, and α,ß-diketoamides. The utility of these compounds was also demonstrated by facile one-pot synthesis of important azaheterocyclic systems.

Gold-Catalyzed Hydrohydrazidation of Terminal Alkynes.

Facile gold-catalyzed hydrohydrazidation of alkynes with various hydrazides R2CONHNH2 (R = Alk or Ar; including those with an additional nucleophilic moiety) in the presence of Ph3PAuNTf2 (6 mol %) leading to a wide range of substituted keto- N-acylhydrazones (18 examples) in excellent to good yields (99-66%) is reported. This novel metal-catalyzed coupling proceeds under mild conditions (chlorobenzene, 60 °C), exhibits high functional group tolerance, and is insensitive to the electronic and steric effects of the substituents in the reactants.

Difference in Energy between Two Distinct Types of Chalcogen Bonds Drives Regioisomerization of Binuclear (Diaminocarbene)PdII Complexes.

The reaction of cis-[PdCl2(CNXyl)2] (Xyl = 2,6-Me2C6H3) with various 1,3-thiazol- and 1,3,4-thiadiazol-2-amines in chloroform gives a mixture of two regioisomeric binuclear diaminocarbene complexes. For 1,3-thiazol-2-amines the isomeric ratio depends on the reaction conditions and kinetically (KRs) or thermodynamically (TRs) controlled regioisomers were obtained at room temperature and on heating, respectively. In CHCl3 solutions, the isomers are subject to reversible isomerization accompanied by the cleavage of Pd-N and C-N bonds in the carbene fragment XylNCN(R)Xyl. Results of DFT calculations followed by the topological analysis of the electron density distribution within the formalism of Bader's theory (AIM method) reveal that in CHCl3 solution the relative stability of the regioisomers (ΔGexp = 1.2 kcal/mol; ΔGcalcd = 3.2 kcal/mol) is determined by the energy difference between two types of the intramolecular chalcogen bonds, viz. S···Cl in KRs (2.8-3.0 kcal/mol) and S···N in TRs (4.6-5.3 kcal/mol). In the case of the 1,3,4-thiadiazol-2-amines, the regioisomers are formed in approximately equal amounts and, accordingly, the energy difference between these species is only 0.1 kcal/mol in terms of ΔGexp (ΔGcalcd = 2.1 kcal/mol). The regioisomers were characterized by elemental analyses (C, H, N), HRESI+-MS and FTIR, 1D (1H, 13C{1H}) and 2D (1H,1H-COSY, 1H,1H-NOESY, 1H,13C-HSQC, 1H,13C-HMBC) NMR spectroscopies, and structures of six complexes (three KRs and three TRs) were elucidated by single-crystal X-ray diffraction.