摘要：2Discovery Process Research, Johnson & Johnson Innovative Medicine, Spring House, PA, USA.

转自：康龙化成

Strategic Atom Replacement Enables Regiocontrol in Pyrazole Alkylation

Alexander Fanourakis

1

,

Yahia

Ali

1

, Liao Chen

1

, Patrick Q. Kelly

1

, Abigail J. Bracken

1

, Christopher B. Kelly

2

& Mark D. Levin

1*

1 Department of Chemistry, University of Chicago, Chicago, IL, USA.

2 Discovery Process Research, Johnson & Johnson Innovative Medicine, Spring House, PA, USA.

—Nature, 2025, 641, 646–652.

Recommended by Bingbing Chang_ MC5

KEYWORDS: Atom replacement, skeletal editing, N-alkylation (反应类型), isothiazoles (反应物), N-alkyl pyrazoles (产物),N-N (成键类型), 2,3-thiadiazine-S-oxides (其他)

ABSTRACT: Pyrazoles are heterocycles commonly found as key substructures in agrochemicals and medicinally active compounds alike. Despite their pervasiveness, established methods fall notably short in delivering complex pyrazoles selectively due to issues of differentiation during either assembly or N-functionalization. This is a direct consequence of a dominant synthetic strategy that attempts to control selectivity determining bonds between poorly differentiated starting materials. To overcome this longstanding challenge, Prof. Mark D. Levin et al here describe a prototypical example of an alternative conceptual approach, ‘strategic atom replacement’, in which synthesize N-alkyl pyrazoles from isothiazoles. The net forward transformation is a ‘swap’ of the isothiazole sulfur atom with a nitrogen atom and its associated alkyl fragment to deliver the alkylated pyrazole. Linking the two azoles is an orphaned heterocycle class, 1,2,3-thiadiazine-S-oxides, whose synthetic potential has yet to be tapped. By proceeding through these unusual heterocycles, the typical selectivity and separation challenges associated with exclusively bond-based pyrazole preparations are circumvented, and even minimally differentiated peripheral substituents can be discriminated to afford isomerically pure products.

TDSO synthesis, alkylation and mechanism

Substrate scope for NH-TDSO alkylation

Selective synthesis of minimally differentiatedN-alkyl pyrazoles and demonstration of further C-N bond-forming reactions

In summary, strategic atom replacement enables the selective synthesis of unsymmetrical N-alkyl pyrazoles from isothiazoles. Implementation of the unusual TDSO heterocycle class confers significant selectivity and separation advantages and has enabled the efficient synthesis of pyrazoles that are notoriously difficult or even impossible to access selectively. This strategy functions smoothly across many C-N bond-forming reactivity modes, including those that are typically not available to the azoles themselves. Retrosynthetically, , Prof. Mark D. Levin’s method demonstrates the value of the strategic atom replacement concept that first fixes the relative position of a placeholder atom in the molecular core, followed by a regiospecific core atom swap that installs the requisite exocyclic substituent with specificity. This two-phase tactic may be more broadly applied to the synthesis of other heterocycles in which traditional bond-based retrosynthesis alone fails to deliver viable strategies or selecitvities.

来源：新浪财经