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. 2020 Feb 7;22(3):1217-1221.
doi: 10.1021/acs.orglett.0c00186. Epub 2020 Jan 24.

Annulation of Hydrazones and Alkynes via Rhodium(III)-Catalyzed Dual C-H Activation: Synthesis of Pyrrolopyridazines and Azolopyridazines

Andrew D Streit  1 , Adam J Zoll  1 , Gia L Hoang  1 , Jonathan A Ellman  1
Affiliations

Annulation of Hydrazones and Alkynes via Rhodium(III)-Catalyzed Dual C-H Activation: Synthesis of Pyrrolopyridazines and Azolopyridazines

Andrew D Streit et al. Org Lett. .

Abstract

Hydrazones readily synthesized from N-aminopyrroles or N-aminoazoles and aldehydes undergo Rh(III)-catalyzed dual C-H activation and coupling with aryl- and alkyl-substituted alkynes to give pyrrolopyridazines or azolopyridazines, respectively. This transformation represents a rare example of hydrazoyl C-H activation and proceeds without heteroatom functionality to direct C-H activation. Hydrazones derived from aromatic, alkenyl, and aliphatic aldehydes were effective inputs, and tethering the alkyne to the hydrazone enabled annulations to more complex, tricyclic products.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Scheme 1.
Scheme 1.
Heterocycle Synthesis by C–H Activation
Scheme 2.
Scheme 2.
Variation of R Substituent in Hydrazone 8a aStandard conditions: 8 (0.30 mmol) and 4a (0.60 mmol); b0.5 M, 0.20 mmol of 8f, 0.40 mmol of 4a. Isolated yields are reported.
Scheme 3.
Scheme 3.
Variation of Pyrrole and Azole Framework in Hydrazone 8a aStandard conditions: 8 (0.30 mmol) and 4a (0.60 mmol). Isolated yields are reported.
Scheme 4.
Scheme 4.
Scope of Alkynesa aStandard conditions: 8a (0.30 mmol) and 4 (0.60 mmol); byield of mixture of regioisomers with regioisomers assigned by 2D NOESY experiments; cCu(OAc)2 in place of AgOAc, omission of PivOH, dioxane (0.2 M) in place of THF, 140 °C (MW), 1 h. Isolated yields are reported.
Scheme 5.
Scheme 5.
Synthesis of Tricyclic Derivatives 10a aStandard conditions: 8 (0.30 mmol). Isolated yields are reported.
Scheme 6.
Scheme 6.
1 mmol Scale Reaction at 1 mol % Precatalyst
Scheme 7.
Scheme 7.
Mechanistic Studies
Scheme 8.
Scheme 8.
Proposed Catalytic Cycle for Annulation
See this image and copyright information in PMC

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