This review which is the second in this series summarises the most common synthetic routes as applied to the preparation of many modern pharmaceutical compounds categorised as containing a six-membered heterocyclic ring. The reported examples are based on the top retailing drug molecules combining synthetic information from both scientific journals and the wider patent literature. It is hoped that this compilation, in combination with the previously published review on five-membered rings, will form a comprehensive foundation and reference source for individuals interested in medicinal, synthetic and preparative chemistry.

https://www.beilstein-journals.org/bjoc/content/pdf/1860-5397-9-265.pdf

An overview of the synthetic routes to the best selling drugs containing 6-membered heterocycles

Condensation polymerization is an important method of polymerization that yields not only engineering plastics such as polyamides, polyesters, and polyimides but also π-conjugated polymers, which have recently received considerable attention with the development of the information technology industry. The molecular weight of those polymers is generally difficult to control, and the polydispersity index theoretically approaches 2 at high conversion, which is unlike the behavior of living polymerization. An uncontrolled molecular weight and broad molecular weight distribution do not stem inherently from the reaction type of condensation polymerization, i.e. condensation steps with elimination of a small molecule species but from a polymerization mechanism for step-growth polymerization. Accordingly, if the mechanism of condensation polymerization could be converted from step-growth to chain-growth, living condensation polymerization would be possible. Nature already uses a chain-growth condensation polymerization process to synthesize perfectly monodisperse biopolymers such as polypeptides,1 DNA,2 and RNA.3 For example, in the biosynthesis of polypeptides, the amino group of an aminoacyl-tRNA, monomer, selectively reacts with the terminal ester moiety of polypeptidyl-tRNA in a ribosome to elongate the peptide chain. Even in artificial condensation polymerization of AB monomers, the chain-growth mechanism could be involved in the following two cases. (1) The change of the substituent effect induced by bond formation of the monomer drives the reactivity of the polymer end group to become higher than that of the monomer (Scheme 1A). (2) In condensation polymerization based on a coupling reaction with a transition metal catalyst, the catalyst is intramolecularly transferred to and activates the elongated polymer end group after the coupling reaction of the monomer with the polymer (Scheme * E-mail: yokozt01@kanagawa-u.ac.jp. Tsutomu Yokozawa was born in Chiba in 1957. He received his B.S. (1981), M.S. (1983), and Ph.D. (1987) degrees in Organic Chemistry from Tokyo Institute of Technology under the direction of Professor Nobuo Ishikawa and Professor Takeshi Nakai. In 1985, he had already started an academic career in the Research Laboratory of Resources Utilization, Tokyo Institute of Technology, as a Research Associate, and he was promoted to Assistant Professor in 1988. He joined the Department of Applied Chemistry, Kanagawa University, as a Lecturer in 1991, and he was promoted to Associate Professor in 1993. During 1997-1998, he worked as a visiting scientist at the University of Illinois at Urbana-Champaign with Professor J. S. Moore. He was promoted to Full Professor in 1999. He was also a researcher for PRESTO, JST, during 2001-2005. He received the Award of the Society of Polymer Science, Japan, in 2007. His research interests cover controlled synthesis of polymers, supramolecular chemistry of polymers, as well as synthetic organic chemistry. Chem. Rev. 2009, 109, 5595–5619 5595

Chain-Growth Condensation Polymerization for the Synthesis of Well-Defined Condensation Polymers and π-Conjugated Polymers

[1] This study investigated long-term chemical aging of model biogenic secondary organic aerosol (SOA) prepared from the ozonolysis of terpenes. Techniques including electrospray ionization mass spectrometry (ESI-MS), UV-visible spectroscopy, Fourier transform infrared (FTIR) spectroscopy, NMR, and three-dimensional fluorescence were used to probe the changes in chemical composition of SOA collected by impaction on substrates and also of aqueous extracts of SOA. The addition of ammonium ions or amino acids to limonene SOA reproducibly produced orange-colored species that strongly absorbed visible radiation and fluoresced at UV and visible wavelengths. Simultaneous addition of H2SO4 to the SOA aqueous extracts inhibited this color transformation. These observations suggest the existence of aging processes leading to heavily conjugated molecules containing organic nitrogen. The presence of nitrogen in the chromophores was confirmed by the dependence of the absorption and fluorescence spectra on the amino acids added. In contrast to the strong change in the absorption and fluorescence spectra, there was no significant change in the ESI-MS, FTIR, and NMR spectra, suggesting that the chromophores were minor species in the aged SOA. Aqueous extracts of aged limonene + NH4+ SOA were characterized by an effective base-e absorption coefficient of ∼3 L g−1 cm−1 at 500 nm. Assuming particulate matter concentrations typical of polluted rural air gives an upper limit of 0.2 M m−1 for the aerosol absorption coefficient due to the aged limonene oxidation products. Biogenic SOA can therefore become weakly absorbing if they undergo aging in the presence of NH4+-containing aerosol.

/pdf/appearance-of-strong-absorbers-and-fluorophores-in-limonene-d8bnncflml.pdf

Appearance of strong absorbers and fluorophores in limonene‐O3 secondary organic aerosol due to NH4+‐mediated chemical aging over long time scales

Transformation of Step-Growth Polymerization into Living Chain-Growth Polymerization.

The current manuscript describes the importance, mechanism propositions, evidence and controversies associated with multicomponent reactions (MCRs). The following multicomponent reactions are presented and critically evaluated: the Biginelli, Hantzsch, Mannich, Passerini and Ugi reactions. The aim of this review is to highlight what we already know about the mechanisms associated with these MCRs and the evidence supporting the proposed reaction pathways. Controversies and prospects are also discussed herein.

/pdf/what-do-we-know-about-multicomponent-reactions-mechanisms-4w5a2cr8z1.pdf

What do we know about multicomponent reactions? Mechanisms and trends for the Biginelli, Hantzsch, Mannich, Passerini and Ugi MCRs

The mechanisms of heterocyclic ring closures

The mechanism of the hantzsch pyridine synthesis: A study by 15N and 13C NMR spectroscopy

Les reactions des acetyl- et benzoylacetates et des α-acetyl- et α-benzoylpropionates avec l'hydroxylamine a pH 10-12 conduisent a des melanges d'isoxazoline-2ones-5 et d'isoxazolols-3

Mechanisms of heterocyclic ring formations. 4. A carbon-13 NMR study of the reaction of .beta.-keto esters with hydroxylamine

The detailed mechanistic pathways are elucidated for the reactions of acetylacetone, methyl acetoacetate, and dimethyl malonate with a variety of amidines and ureas. In many cases the identificatio...

Taher I. Yousaf

Papers

The mechanisms of heterocyclic ring closures

The mechanism of the hantzsch pyridine synthesis: A study by 15N and 13C NMR spectroscopy

Mechanisms of heterocyclic ring formations. 4. A carbon-13 NMR study of the reaction of .beta.-keto esters with hydroxylamine

A C-13 nuclear magnetic resonance study of the pyrimidine synthesis by the reactions of 1,3-dicarbonyl compounds with amidines and ureas

An h-1, c-13 and n-15 nmr study of the paal-knorr condensation of acetonylacetone with primary amines