Commercial metal–organic frameworks as heterogeneous catalysts

Perchloric acid adsorbed on silica gel as a new, highly efficient, and versatile catalyst for acetylation of phenols, thiols, alcohols, and amines

Catalyst-Free Conjugated Addition of Thiols to α,β-Unsaturated Carbonyl Compounds in Water

Soluble guanylate cyclase (sGC) is a key signal-transduction enzyme activated by nitric oxide (NO). Impairments of the NO-sGC signaling pathway have been implicated in the pathogenesis of cardiovascular and other diseases. Direct stimulation of sGC represents a promising therapeutic strategy particularly for the treatment of pulmonary hypertension (PH), a disabling disease associated with a poor prognosis. Previous sGC stimulators such as the pyrazolopyridines BAY 41-2272 and BAY 41-8543 demonstrated beneficial effects in experimental models of PH, but were associated with unfavorable drug metabolism and pharmacokinetic (DMPK) properties. Herein we disclose an extended SAR exploration of this compound class to address these issues. Our efforts led to the identification of the potent sGC stimulator riociguat, which exhibits an improved DMPK profile and exerts strong effects on pulmonary hemodynamics and exercise capacity in patients with PH. Riociguat is currently being investigated in phase III clinical trials for the oral treatment of PH.

Discovery of Riociguat (BAY 63-2521): A Potent, Oral Stimulator of Soluble Guanylate Cyclase for the Treatment of Pulmonary Hypertension

Several new ligands, azoimidazoles belonging to the class 1-methyl-2-(arylazo)imidazoles (L1 (3)) and 1-benzyl-2-(arylazo)imidazoles (L2 (4)) (R = H (a), Me (b), OMe (c), Cl (d), NO2 (e)) have been synthesized and reacted with RuCl3 in ethanol under refluxing conditions. Two isomers of the composition RuL2Cl2, green (i) and blue (iii), are chromatographically separated. The green isomer is quantitatively transformed to the blue isomer on refluxing in a high boiling solvent. The isomeric structures have been confirmed by X-ray crystallography. Crystal data are as follows. Green complex C38H34Cl2N8Ru (6a):  crystal system monoclinic; space group C2/c; a = 15.680(8) A; b = 22.766(14) A; c = 11.473(5) A; β = 119.27(4)°; V = 3573(3) A3 Z = 4; R = 3.59%; Rw = 4.38%. Blue complex C22H24Cl2N8Ru (7b):  crystal system monoclinic; space group P21/n, a = 9.547(6) A; b = 22.554(14) A; c = 11.748(8) A; β = 99.07(5)°; V = 2498(3) A3; Z = 4; R = 3.15%; Rw = 4.51%. With reference to the pairs of Cl, N(imidazole), and N(az...

Chemistry of Azoimidazoles: Synthesis, Spectral Characterization, Electrochemical Studies, and X-ray Crystal Structures of Isomeric Dichloro Bis[1-alkyl-2-(arylazo)imidazole] Complexes of Ruthenium(II)

Thiolate anions have been generated in a "demand-based" fashion under virtually neutral conditions for chemoselective deprotection of aryl alkyl ethers. Solvents play the critical role in making the reaction effective and should have high values of epsilon (>30), molecular polarizabilities (>10), and DN (>27) and low values of AN ( methyl > ethyl. Electron-withdrawing substituents increase the rate of ether cleavage reaction. The influence of the steric and electronic factors have been successfully exploited for selective deprotection of aryl alkyl ethers during inter- and intramolecular competitions.

Demand-based thiolate anion generation under virtually neutral conditions: influence of steric and electronic factors on chemo- and regioselective cleavage of aryl alkyl ethers.

The nucleophilicity of arenethiols can be augmented via hydrogen bonding with ‘naked' halide anion. The activity of the halide anions follow the order F- ≫ Cl- ∼ Br- ∼ I- and is dependent on the countercation (Bu4N ∼ Cs ∼ K > Na ≫ Li). The solvent plays an important role in nucleophilic activation as well as regeneration of the effective nucleophile (e.g. ArS-) and those with high dielectric constant, high molecular polarizability, high donor number (DN), and low acceptor number (AN) are the most effective. Selective deprotection of alkyl/aryl esters and aryl alkyl ethers can be achieved under nonhydrolytic and neutral conditions by the treatment with thiophenol in 1-methyl-2-pyrrolidone (NMP) in the presence of a catalytic amount of KF. Aryl esters are selectively deprotected in the presence of alkyl esters and alkyl methyl ethers during intramolecular competitions.

Influence of hydrogen bonding in the activation of nucleophiles: PhSH-(catalytic) KF in N-methyl-2-pyrrolidone as an efficient protocol for selective cleavage of alkyl/aryl esters and aryl alkyl ethers under nonhydrolytic and neutral conditions.

Chemoselective O-methylation of phenols under non-aqueous condition

Aryl methyl ethers, methyl esters, aryl esters, and aryl sulfonates are chemoselectively deprotected under nonhydrolytic conditions by treatment with Ph(2)S(2) (0.6 equiv) and Na (1.6 equiv) in NMP under reflux or at 90 degrees C. Quantitative utilization of the 'PhS' moiety as the effective nucleophilic species represents conservation of atom economy. Other solvents such as HMPA, DMPU, DMEU, and DMF afforded comparable results. Chloro, nitro, aldehyde, alpha,alpha-diketone, and alpha,beta-unsaturated ketone functionalities remain unaffected. The deprotection was found to take place in the order aryl ester > alkyl ester > aryl alkyl ether. Substrates bearing strong electron-withdrawing groups react at a faster rate than those not having such substitution. The differences in rate of reaction has been exploited for selective deprotection for intramolecular competition. An aryl acetate/benzoate is deprotected selectively in preference to a methyl ester or aryl methyl ether. Selective deprotection of a methyl ester is observed in the presence of an aryl alkyl ether.

Diphenyl Disulfide and Sodium in NMP as an Efficient Protocol for in Situ Generation of Thiophenolate Anion: Selective Deprotection of Aryl Alkyl Ethers and Alkyl/Aryl Esters under Nonhydrolytic Conditions†,‡

Mrinal K. Nayak

Papers

Demand-based thiolate anion generation under virtually neutral conditions: influence of steric and electronic factors on chemo- and regioselective cleavage of aryl alkyl ethers.

Influence of hydrogen bonding in the activation of nucleophiles: PhSH-(catalytic) KF in N-methyl-2-pyrrolidone as an efficient protocol for selective cleavage of alkyl/aryl esters and aryl alkyl ethers under nonhydrolytic and neutral conditions.

Chemoselective O-methylation of phenols under non-aqueous condition

Diphenyl Disulfide and Sodium in NMP as an Efficient Protocol for in Situ Generation of Thiophenolate Anion: Selective Deprotection of Aryl Alkyl Ethers and Alkyl/Aryl Esters under Nonhydrolytic Conditions†,‡

Chemoselective aryl alkyl ether cleavage by thiophenolate anion through its in situ generation in catalytic amount