Application of the Baylis-Hillman methodology in the construction of novel heterocyclic derivatives

Baylis-Hillman reactions of 2,2’-dithiodibenzaldehyde with the acyclic alkenes, methyl vinyl ketone (MVK) and methyl acrylate have afforded the thiochromene derivatives in moderate yields, and this approach has been extended to the use of the cyclic alkenes, 2-cyclohexenone and 2-cyclopentenone to afford the tricyclic analogues. In all cases, reduction of the disulphide link and intramolecular cyclisation occurred in situ, and a preliminary kinetic study of this reaction using the acyclic substrates MVK and methyl acrylate was undertaken with the aim of elucidating the mechanism involved. The results obtained showed that the consumption of both 2,2’-dithiodibenzaldehyde and MVK and/or methyl acrylate followed 1st-order kinetics during the initial stages of the reaction, but then deviated from 1st-order linearity. The reaction with methyl acrylate was much slower than with MVK, and the kinetic data indicates the mechanism to be more complex than anticipated. Conjugate addition reactions of methyl acrylate-derived 2-nitrobenzaldehyde Baylis-Hillman adducts with the amines, piperidine and benzylamine, afforded a range of conjugate addition products as diastereomeric mixtures in excellent yield (80-100%). Catalytic hydrogenation of the conjugate addition products using a Pd-C catalyst in ethanol, has afforded the corresponding, novel 3-amino-2-quinolone derivatives in lower yield (22-37%).The application of [superscript 13]C NMR prediction programmes to selected compounds synthesized in this study has revealed reasonable correlations between the experimental and predicted values

Mechanistic studies of unusual Miruta-Baylis-Hillman reactions

This study has focussed on the application of synthetic, kinetic and exploratory theoretical methods in elucidating the reaction mechanisms of four Morita-Baylis-Hillman (MBH) type reactions, viz, i) the reactions of the disulfide 2,2'-dithiodibenzaldehyde with various activated alkenes in the presence of DBU and Ph₃P, ii) the reactions of chromone-3-carbaldehydes with MVK, iii) the reactions of chromone-2-carbaldehydes with acrylonitrile and iv) with methyl acrylate. Attention has also been given to the origin of the observed regioselectivity in Michaelis-Arbuzov reactions of 3-(halomethyl)coumarins. Cleavage of the sulfur-sulfur bond of aryl and heteroaryl disulfides by the nitrogen nucleophile DBU has been demonstrated, and a dramatic increase in the rate of tandem MBH and disulfide cleavage reactions of 2,2'-dithiodibenzaldehyde with the activated alkenes, MVK, EVK, acrylonitrile, methyl acrylate and tert-butyl acrylate has been achieved through the use of the dual organo-catalyst system, DBU-Ph₃P – an improvement accompanied by an increase in the yields of the isolated products. Detailed NMR-based kinetic studies have been conducted on the DBU-catalysed reactions of 2,2'-dithiodibenzaldehyde with MVK and methyl acrylate, and a theoretical kinetic model has been developed and complementary computational studies using Gaussian 03, at the DFT-B3LYP/6-31G(d) level of theory have provided valuable insights into the mechanism of these complex transformations. Reactions of chromone-3-carbaldehydes with MVK to afford chromone dimers and tricyclic products have been repeated, and a novel, intermediate MBH adduct has been isolated. The mechanisms of the competing pathways have been elucidated by DFT calculations and the development of a detailed theoretical kinetic model has ensued. Unusual transformations in MBH-type reactions of chromone-2-carbaldehydes with acrylonitrile and methyl acrylate have been explored and the structures of the unexpected products have been established using 1- and 2-D NMR, HRMS and X-ray crystallographic techniques. Attention has also been given to the synthesis of 3-(halomethyl)coumarins via the MBH reaction, and their subsequent Michaelis-Arbuzov reactions with triethyl phosphite. An exploratory study of the kinetics of the phosphonation reaction has been undertaken and the regio-selectivity of nucleophilic attack at the 4- and 1'-positions in the 3-chloro- and 3-(iodomethyl)coumarins has been investigated by calculating Mulliken charges, LUMO surfaces and Fukui condensed local softness functions

Mechanistic studies of unusual Miruta-Baylis-Hillman reactions

This study has focussed on the application of synthetic, kinetic and exploratory theoretical methods in elucidating the reaction mechanisms of four Morita-Baylis-Hillman (MBH) type reactions, viz, i) the reactions of the disulfide 2,2'-dithiodibenzaldehyde with various activated alkenes in the presence of DBU and Ph₃P, ii) the reactions of chromone-3-carbaldehydes with MVK, iii) the reactions of chromone-2-carbaldehydes with acrylonitrile and iv) with methyl acrylate. Attention has also been given to the origin of the observed regioselectivity in Michaelis-Arbuzov reactions of 3-(halomethyl)coumarins. Cleavage of the sulfur-sulfur bond of aryl and heteroaryl disulfides by the nitrogen nucleophile DBU has been demonstrated, and a dramatic increase in the rate of tandem MBH and disulfide cleavage reactions of 2,2'-dithiodibenzaldehyde with the activated alkenes, MVK, EVK, acrylonitrile, methyl acrylate and tert-butyl acrylate has been achieved through the use of the dual organo-catalyst system, DBU-Ph₃P – an improvement accompanied by an increase in the yields of the isolated products. Detailed NMR-based kinetic studies have been conducted on the DBU-catalysed reactions of 2,2'-dithiodibenzaldehyde with MVK and methyl acrylate, and a theoretical kinetic model has been developed and complementary computational studies using Gaussian 03, at the DFT-B3LYP/6-31G(d) level of theory have provided valuable insights into the mechanism of these complex transformations. Reactions of chromone-3-carbaldehydes with MVK to afford chromone dimers and tricyclic products have been repeated, and a novel, intermediate MBH adduct has been isolated. The mechanisms of the competing pathways have been elucidated by DFT calculations and the development of a detailed theoretical kinetic model has ensued. Unusual transformations in MBH-type reactions of chromone-2-carbaldehydes with acrylonitrile and methyl acrylate have been explored and the structures of the unexpected products have been established using 1- and 2-D NMR, HRMS and X-ray crystallographic techniques. Attention has also been given to the synthesis of 3-(halomethyl)coumarins via the MBH reaction, and their subsequent Michaelis-Arbuzov reactions with triethyl phosphite. An exploratory study of the kinetics of the phosphonation reaction has been undertaken and the regio-selectivity of nucleophilic attack at the 4- and 1'-positions in the 3-chloro- and 3-(iodomethyl)coumarins has been investigated by calculating Mulliken charges, LUMO surfaces and Fukui condensed local softness functions

Heterometallic half-sandwich complexes containing a ferrocenyl motif: Synthesis, molecular structure, electrochemistry and antiplasmodial evaluation

The synthesis and characterisation of a series of new half-sandwich ruthenium(II), rhodium(III) and iridium(III) heterometallic complexes containing a ferrocenyl motif is reported. The dinuclear complexes were prepared by reaction of the ferrocenyl–salicylaldimine complex (1) with either [Ru(p-cymene)Cl2]2, [Rh(C5Me5)Cl2]2 or [Ir(C5Me5)Cl2]2 to yield heterobimetallic complexes where complex 1 acts as a bidentate anionic donor to ruthenium, rhodium or iridium via the imine nitrogen and phenolic oxygen atoms. The structures of the compounds have been confirmed using a variety of spectroscopic and analytical techniques, including single crystal X-ray diffraction analysis of complexes 2–4. The electrochemical behaviour of the heterometallic complexes was examined using cyclic voltammetry and a positive shift in the half-wave potential (E1/2) of the ferrocene/ferrocenium couple was observed for the Platinum Group Metal (PGM) complexes, indicating that the ferrocenyl moiety becomes harder to oxidise. The complexes were evaluated for antiplasmodial activity in vitro against the chloroquine-sensitive Plasmodium falciparum strain NF54, yielding IC50 values in the low micromolar range. Further analysis of complexes 1–4 using a β-hematin inhibition assay revealed that these complexes are able to inhibit the formation of synthetic hemozoin