Synthesis of Di-, Tri-, and Tetrasubstituted Pyridines from (Phenylthio)carboxylic Acids and 2-[Aryl(tosylimino)methyl]acrylates

Abstract

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...

Synthesis of Heterocycles by isothiourea organocatalysis

“…The three steps protocol opens access to tri and tetra‐substituted pyridine tosylates in moderate to good yields (Scheme 36). [ 42 ]…”

Isothiourea‐Catalyzed Synthesis of Pyrrole‐ and Indole‐Functionalized Tetrasubstituted Pyridines

“…Thermally‐promoted N‐ to O‐sulfonyl transfer then gave the final pyridine product (Scheme b). This approach has since been extended by ourselves, and others, to utilize alternative α‐leaving groups and tolerate different substitution patterns.…”

Generation and Reactivity of C(1)‐Ammonium Enolates by Using Isothiourea Catalysis

“…In 2014, the Michael addition/lactonisation methodology was incorporated into a sequence for the synthesis of di‐, tri‐ and tetrasubstituted pyridines (Scheme 8). [30] Following the formal [4+2] cycloaddition between (phenylthio)acetic acids 27 and α,β‐unsaturated ketimines 22 catalysed by achiral isothiourea DHPB 28 to give dihydropyridinone products 29 , treatment with m ‐CPBA yielded the desired sulfoxides 30 , which underwent elimination on warming to room temperature. The pyridones 31 were heated at 80 °C to provide the pyridine products 32 .…”