133659-66-2Relevant academic research and scientific papers
Demonstrating the Synergy of Synthetic, Mechanistic, and Computational Studies in A Regioselective Aniline Synthesis
Davies, Ian W.,Marcoux, Jean-Francois,Kuethe, Jeffery T.,Lankshear, Michael D.,Taylor, Jeremy D. O.,Tsou, Nancy,Dormer, Peter G.,Hughes, David L.,Houk,Guner, Vildan
, p. 1298 - 1308 (2007/10/03)
Tri- and tetrasubstituted anilines are formed in good to excellent yields by the addition of ketones to vinamidinium salts (up to 98%). The reaction proceeds via the formation of dienone intermediates, which react to form an enamine with the liberated amine. In the case of a nitro, or dimethylaminomethylene substituent, the enamines undergo a facile electrocyclic ring closure to form a cyclohexadiene, which goes on to form anilines with a high degree of selectivity (up to 50:1) with a minor competing pathway proceeding via the enol providing phenols. Competition experiments using isotopic substitution reveal that the rate determining step en route to dienone is enol/enolate addition to the vinamidinium salt, which is characterized by an inverse secondary isotope effect (kH/D 0.7-0.9). Computational studies have been used to provide a framework for understanding the reaction pathway. The original proposal for a [1,5]-H shift was ruled out on the basis of the calculations, which did not locate a thermally accessible transition state. The minimum energy conformation of the enamine is such that a facile electrocyclic ring closure is ensured, which is corroborated by the experimental studies. A framework for understanding the reaction pathway is presented.
Repaglinide and related hypoglycemic benzoic acid derivatives
Grell, Wolfgang,Hurnaus, Rudolf
, p. 5219 - 5246 (2007/10/03)
The structure-activity relationships in two series of hypoglycemic benzoic acid derivatives (5, 6) were investigated. Series 5 resulted from meglitinide (3) when the 2-methoxy was replaced by an alkyleneimino residue. Maximum activity was observed with the cis-3,5-dimethylpiperidino (5h) and the octamethyleneimino (5l) residues. Series 6 resulted from the meglitinide analogon 4 bearing an inversed amido function when the 2-methoxy, the 5- fluoro, and the α-methyl residue were replaced by a 2-piperidino, a 5- hydrogen, and a larger α-alkyl residue, respectively. An alkoxy residue ortho to the carboxy group further increased activity and duration of action in the rat. The most active racemic compound, 6al (R4 = isobutyl; R = ethoxy), turned out to be 12 times more active than the sulfonylurea (SU) glibenclamide (1). Activity was found to reside predominantly in the (S)- enantiomers. Compared with the SUs 1 and 2 (glimepiride), the most active enantiomer, (S)-6al (AG-EE 623 ZW; repaglinide; ED50 = 10 μg/kg po), is 25 and 18 times more active. Repaglinide turned out to be a useful therapeutic for type 2 diabetic patients; approval was granted recently by the FDA and the EMEA. From investigations on the pharmacophoric groups in compounds of type 5 and 6, it was concluded that in addition to the two already known - the acidic group (COOH; S02NH) and the amidic spacer (CONH; NHCO) - the ortho residue R1 (alkyleneimino; alkoxy; oxo) must be regarded as a third one. A general pharmacophore model suitable for hypoglycemic benzoic acid derivatives, SUs, and sulfonamides is proposed (Figure 6). Furthermore, from superpositions of low-energy conformations (LECs) of 1, 2, and (S)-6al, it was concluded that a common binding conformation (LEC II; Figure 10B) may exist and that differences in binding to the SU receptor and in the mechanism of insulin release between repaglinide and the two SUs may be due to specific hydrophobic differences.
