3‐Hydroxy‐2‐cyanoalk‐2‐enamides, and 2‐Cyano‐2‐(tetrahydrofuran‐2‐ylidene)‐ and 2‐Cyano‐2‐(tetrahydropyran‐2‐ylidene)acetamides: Synthesis, structure, and solvent‐dependent (Z)/(E)‐isomerism

Abstract

Dedicated to Professor D. Srehuck on the occasion of his 60th birthday 3-Hydroxy-2-cyanoalk-2-enamides, and 2-cyano-2-(tetrahydrofuran-2-ylidene)-and 2-cyano-2-(tetrahydropyran-2-y1idene)acetamides with N-alkyl and N-aryl substituents have been synthesized in three steps from cyanoacetic acid. Their conformations were investigated by X-ray crystallography and 'H-NMR ROESY spectroscopy at room temperature. The enolic compounds 1-3 adopt an extended conformation stabilized by a strong intramolecular 0 -H ... O=C bond both in the solid state and in (D,)DMSO solution. In contrast, the structure of the cyclic derivatives 5a,bbSa,b is solvent-dependent. In the solid state and in CDCI, solution, the compounds adopt an extended conformation of type I or 111, while, in (D,)DMSO solution, their structures undergo time-dependent (Z)/(E)-isomerization structures (of type 11 or IV). This observation is compatible with a dipolar transition state of rotation. The kinetics of the isomerization are controlled by the N-substituent, the N-(r-Bu) derivatives 7a and 7b having the highest barrier of rotation around the C = C bond. The whole body ofexperimental evidence together with the results of molecular-mechanics calculations with I -IV, indicate that, in DMSO, two (E)/(Z)-isomers with two conformations are present, and that they undergo interconversion at room temperature with four different constants. The very fast exchange rates k,,,, and k,,,,,, in the NMR time-scale might be responsible for the detection of only two isomers.

On the interactions of leflunomide and teriflunomide within receptor cavity — NMR studies and energy calculations

“…As we have mentioned in the introductory section, previous studies on the structure of teriflunomide 2 suggested that compound 2 and some of its analogues existed mainly in a Z configuration stabilized by a strong intramolecular hydrogen bond (Scheme 1 ) [ 30 – 32 ]. Other reports, both experimental and theoretical, pointed out that the active form of teriflunomide was the Z configuration lacking the internal hydrogen contact [ 14 , 17 ].…”

“…Previous studies showed that teriflunomide 2 also interacts with arginine through a water molecule in the active site of DHODH [ 30 – 32 ]. To examine whether this is a significant feature, we optimized the adducts of compound 2 with water, in which a single molecule of water interacted separately with the OH, NH, and CO groups of 2 .…”

Synthesis of N-Substituted γ-Methylene γ-Lactams

“…Cyanoacetamides were prepared by applying methods described in the literature, usually by heating an amine with ethyl cyanoacetate [7] (Method A) or by condensation with cyanoacetic acid in the presence of diisopropyl carbodiimide [8,9] (Method B).…”