Three-Component Coupling of Aldehydes, Aminopyrazoles, and Sulfoxonium Ylides via Rhodium(III)-Catalyzed Imidoyl C-H Activation: Synthesis of Pyrazolo[1,5- a]pyrimidines

Abstract

An efficient, three-component strategy for Rh(III)-catalyzed annulation of readily available 3-aminopyrazoles, aldehydes, and sulfoxonium ylides to give diverse pyrazolo[1,5- a]pyrimidines is disclosed. The reactions were performed under straightforward benchtop conditions using microwave heating with short reaction times. Good yields were obtained for many substituted aminopyrazoles and a very large variety of aromatic and heteroaromatic aldehydes, including those incorporating electron-withdrawing, electron-donating, basic nitrogen, halide and acidic functionality. Ester and methoxy functionalities could also be directly installed on the pyrimidine ring by employing ethyl glyoxylate and trimethyl orthoformate in place of the aldehyde, respectively. In addition, a range of sulfoxonium ylides provided products in good yields to establish that aryl, heteroaryl, and branched and unbranched alkyl substituents can be introduced with this reagent. Finally, the first use of a formyl sulfoxonium ylide in a chemical transformation enabled the preparation of products with only a single substituent on the pyrimidine ring as introduced by the aldehyde coupling partner. For the formyl ylide, a one-pot, stepwise reaction sequence was used to prevent competitive condensation of the formyl group with the aminopyrazole.

Scheme 1.

Fused [5,6]-Bicyclic Bridgehead Nitrogen Heterocycle Synthesis

Scheme 2.

Aldehyde Scope for Three-component Synthesis of Pyrazolopyrimidines 8^{a a} Standard conditions with 5 (0.60 mmol), 6a (0.30 mmol), and 7a (0.45 mmol). ^b 0.2 M.

Scheme 3.

Sulfoxonium Ylide Scope for Three-Component Synthesis of Pyrazolopyrimidines 8^{a a} Standard conditions with 5a (0.60 mmol), 6a (0.30 mmol), and 7 (0.45 mmol)

Scheme 4.

Aminopyrazole Scope for Three-Component Synthesis of Pyrazolopyrimidines 8^{a a} Standard conditions with 5a (0.60 mmol), 6 (0.30 mmol), and 7a (0.45 mmol). ^b 0.2 M

Scheme 5.

Annulations with Formyl Ylide to Give Pyrazolopyrimidines 8^{a a} Standard conditions 5 (0.60 mmol), 6 (0.30 mmol), 7i (0.33 mmol). ^b 0.4 M. ^c 0.1 M

Scheme 6.

Ethyl Glyoxylate as the Aldehyde^{a a} 5p (0.60 mmol), 6a (0.30 mmol), 7 (0.45 mmol). ^b 7i (1.1 equiv).

Scheme 7.

Methoxy Group Introduction^{a a} 5q (3.0 mmol), 6a (0.30 mmol), 7 (0.45 mmol). ^b 7i (1.1 equiv).

Scheme 8.

Benchtop Reaction Set Up at 1 mmol Scale

Scheme 9.

Proposed Mechanism for Annulation