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. 2023 Dec 15;25(49):8797-8802.
doi: 10.1021/acs.orglett.3c03325. Epub 2023 Dec 1.

Asymmetric Dearomatization of Phthalazines by Anion-Binding Catalysis

Marta Velázquez  1 , Rosario Fernández  1 , José M Lassaletta  2 , David Monge  1
Affiliations

Asymmetric Dearomatization of Phthalazines by Anion-Binding Catalysis

Marta Velázquez et al. Org Lett. .

Abstract

A straightforward methodology for the enantioselective synthesis of 1,2-dihydrophthalazines via dearomatization of phthalazines by anion-binding catalysis has been developed. The process involves the Mannich-type addition of silyl ketene acetals to in situ generated N-acylphthalazinium chlorides using a tert-leucine derived thiourea as a H-bond donor catalyst. Ensuing selective and high-yielding transformations provide appealing dihydro- and tetrahydro-phthalazines, phthalazones, and piperazic acid homologues, en route to biologically relevant molecules.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Selective bioactive diazaheterocycles.
Scheme 1
Scheme 1. Catalytic Asymmetric Dearomatization of Phthalazines
Scheme 2
Scheme 2. Optimization of Acylating Reagents
(a) Reactions performed at 0.2 mmol scale. Yields given for isolated products after chromatography. ee’s were determined by HPLC on chiral stationary phases. (b) Reaction performed with 5 mol % of catalyst loading.
Figure 2
Figure 2
Noncatalyzed vs catalyzed reaction kinetics. Reactions were performed in MTBE with 5 mol % of catalyst from −78 to 10 °C.
Scheme 3
Scheme 3. Substrate Scope
(a) Reactions performed at 0.2 mmol scale. (b) Reaction performed at 1 mmol scale. (c) 2.5 equiv of 2a. (d) 10 mol % of catalyst loading.
Scheme 4
Scheme 4. Transformations of Dihydrophthalazines 8
See this image and copyright information in PMC

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