Three-Component Coupling of Aldehydes, 2-Aminopyridines, and Diazo Esters via Rhodium(III)-Catalyzed Imidoyl C-H Activation: Synthesis of Pyrido[1,2- a]pyrimidin-4-ones

Abstract

Imines formed in situ from 2-aminopyridines and aldehydes undergo Rh(III)-catalyzed imidoyl C-H activation and coupling with diazo esters to give pyrido[1,2- a]pyrimidin-4-ones. Aromatic and enolizable aliphatic aldehydes were both effective substrates, and a broad range of functional groups were incorporated at different sites on the heterocyclic products. In addition, methoxy and dimethylamino functionalities could be directly installed on the pyrimidine ring by employing trimethyl orthoformate or N, N-dimethylformamide dimethyl acetal in place of the aldehyde, respectively.

Scheme 1.

Heterocycle Synthesis by Imidoyl C–H Activation

Scheme 2.. Scope of Aliphatic Aldehydes.^a

^aStandard conditions: 8a (0.30 mmol), 5 (0.60 mmol), and 9a (0.45 mmol). ^b10 equiv (3.0 mmol) trimethyl orthoformate was used in place of 5; no molecular sieves. ^c1.1 equiv (0.33 mmol) N,N-dimethylformamide dimethyl acetal in place of 5. Isolated yields are reported.

Scheme 3.. Scope of Aromatic Aldehydes.^a

^aStandard conditions: 8a (0.30 mmol), 5 (0.60 mmol), and 9a (0.45 mmol). Isolated yields are reported.

Scheme 4.. Influence of the Substitution Pattern of the Employed 2-Aminopyridines^a

^aStandard conditions: 8 (0.30 mmol), 5a (0.60 mmol), and 9a (0.45 mmol). Isolated yields are reported.

Scheme 5.. Scope of Diazo Esters^a

^aStandard conditions: 8a (0.30 mmol), 5a (0.60 mmol), and 9 (0.45 mmol). ^bThree equiv of diazophosphonate 9f (0.90 mmol) were used. Isolated yields are reported.

Scheme 6.

A 2 mmol Scale Reaction at 5 mol % Catalyst

Scheme 7.

Product Diversification

Scheme 8.

Proposed Catalytic Cycle for Annulation