Single point activation of pyridines enables reductive hydroxymethylation

Abstract

Pyridines can be activated at a single point with a new benzyl group, followed by dearomative functionalisation at C3 using formaldehyde.

Recent advances in the dearomative functionalisation of heteroarenes

“…7 The value of the methodology was also demonstrated when we applied it in a short and efficient synthesis of the anti-depressant pharmaceutical paroxetine. 8 The group of Zhang recently disclosed some remarkable cascade reactions under similar conditions, functionalising reactive iminium species formed in situ through intramolecular trapping reactions. In 2021 a protocol for the incorporation of substituted phenols onto heterocycles was published (see 6 / 12, Scheme 4).…”

“…Mechanistically, the intermediate 32, formed aer dearomatisation by hydride at C-2 and formaldehyde alkylation at C-3 is able to lose water and form an extended iminium Scheme 3 Reductive hydroxymethylation of 4-aryl and 4-heteroaryl pyridinium salts. 7,8 Scheme 4 Catalytic reductive tandem functionalisation of quinolinium salts with phenols and formaldehyde. 9 Scheme 5 Catalytic annulation of isoquinolines with 1,3-dicarbonyl compounds and formaldehyde.…”

“… 7 The value of the methodology was also demonstrated when we applied it in a short and efficient synthesis of the anti-depressant pharmaceutical paroxetine. 8 …”

Facile Synthesis of 2-Methylnicotinonitrile through Degenerate Ring Transformation of Pyridinium Salts

“…4-(4-(tert-butyl)phenyl)pyridine (1g). 25 White solid. (1.014 g, 96%) 1 H NMR (400 MHz, CDCl 3 ) δ 8.67 (s, 2H), 7.71− 7.44 (m, 6H), 1.39 (s, 9H).…”

“…4-(4-Methoxyphenyl)pyridine (1h). 25 White solid. (879.8 mg, 95%) 1 H NMR (400 MHz, CDCl 3 ) δ 8.64 (s, 2H), 7.65− 7.59 (m, 2H), 7.49 (d, J = 5.9 Hz, 2H), 7.07−6.99 (m, 2H), 3.88 (s, 3H).…”