Acids to bases: The synthesis of 2,4,6‐trisubstituted pyridines from (phenylthio)acetic acid and a range of α,β‐unsaturated ketimines is reported. This process proceeds by intermolecular Michael addition/lactamization, thiophenol elimination, and N‐ to O‐sulfonyl migration, giving 2‐sulfonate‐substituted pyridines which are readily derivatized to generate structural diversity.

N-Acyl imidazoles and catalytic isothiourea hydrochloride salts function as ammonium enolate precursors in the absence of base. Enantioselective Michael addition-cyclization reactions using different α,β-unsaturated Michael acceptors have been performed to form dihydropyranones and dihydropyridinones with high stereoselectivity. Detailed mechanistic studies using RPKA have revealed the importance of the "imidazolium" effect in ammonium enolate formation and have highlighted key differences with traditional base-mediated processes.

Isothiourea HBTM-2.1 catalyses the Michael addition-lactonisation of 2-aryl and 2-alkenylacetic acids and α,β-unsaturated trichloromethyl ketones. Ring-opening of the resulting dihydropyranones and subsequent alcoholysis of the CCl3 ketone with an excess of methanol gives a range of diesters in high diastereo- and enantioselectivity (up to 95 : 5 dr and >99% ee). Sequential addition of two different nucleophiles to a dihydropyranone gives the corresponding differentially substituted diacid derivative.

An isothiourea-catalyzed Michael additionlactamization followed by sulfide oxidation-elimination/N-to Osulfonyl transfer sequence for the formation of 2,3,5-and 2,3-substituted pyridine 6-tosylates from (phenylthio)acetic acids and α,β-unsaturated ketimines is described. Incorporation of the valuable 2-sulfonate group allows derivatization to a range of di-, tri-, and tetra-substituted pyridines.The pyridine motif is a heterocycle class that forms the core of many biologically-active molecules and is widespread in both agrochemicals and pharmaceuticals. [1] Due to the broad synthetic and medicinal application of these molecules there has been much effort directed towards their synthesis. [2,3] Despite these advances, the catalytic preparation of diverse and highly functionalized pyridines from easily accessible starting materials still remains a key focus within the synthetic community. Following the seminal nucleophilic-catalyzed aldol lactonization (NCAL) work by Romo and co-workers using ammonium enolates [4] generated from carboxylic acids, [5] we have previously used isothioureas [6] to catalyze the Michael addition-lactonization/lactamization of arylacetic and alkenylacetic acids with electron-deficient Michael acceptors. [7] This strategy was used to produce 2,4,6-substituted pyridines from (phenylthio)acetic acid via a Michael addition-lactamization/PhSH-elimination/N-to Osulfonyl transfer cascade sequence (Scheme 1a). [8] To extend this methodology beyond 2,4,6-substituted pyridines, alkyl 2-[aryl(tosylimino)methyl]acrylates were identified as potential Michael acceptors to access 2,3,6-substituted pyridines. Additionally, while α,α-disubstituted acetic acids are typically recalcitrant in this methodology, we envisioned that the absence of a β-substituent in the Michael acceptor may facilitate their use and provide access to 2,3,5,6-functionalized pyridines (Scheme 1b). To investigate this route to diversely functionalized pyridines, a series of alkyl 2-[aryl(tosylimino)methyl]acrylates were prepared. [9] Model studies treated (phenylthio)acetic acid 1 with pivaloyl chloride to make the corresponding mixed anhydride in situ, which upon treatment with DHPB (3,4-dihydro-2H-pyrimido[2,1-b]benzothiazole) 2 (20 mol %) and excess i-Pr 2 NEt at room temperature promoted Scheme 1. Isothiourea-mediated synthesis of pyridines Michael addition-lactamization with ketimine 3 to give dihydropyridinone 4 in 70% yield after 1 h (Scheme 2). [10] In contrast to our previous studies, PhSH elimination was not observed in this reaction process either at elevated temperatures or in the presence of excess Et 3 N. These observations are in congruence with those of Donohoe and coworkers in a related system. [11] It was therefore envisioned that a sulfide oxidation-elimination and thermal-assisted Nto O-sulfonyl transfer could be used to produce the desired pyridines. [12--13] Pleasingly, the oxidation of dihydropyridinone 4 with m-CPBA (1.1 equiv) and excess Na 2 CO 3 in CH 2 Cl 2 at 0 o C gave the desired sulf...

The catalytic enantioselective synthesis of a range of trans-dihydropyridinones from aryl-, heteroaryl- and alkenylacetic acids and saccharin-derived ketimines with good to excellent stereocontrol (15 examples, up to >95 : 5 dr, up to >99 : 1 er) is reported. After extensive optimisation, HyperBTM proved the optimal isothiourea catalyst for this transformation at -78 °C, giving trans-dihydropyridones with generally excellent levels of diastereo- and enantioselectivity.