Deconstructive Pyridylation of Unstrained Cyclic Amines through a One-Pot Umpolung Approach

Hong, Seonghyeok; Kweon, Byeongseok; Lee, Wooseok; Chang, Sukbok; Hong, Sungwoo

doi:10.1021/acs.orglett.3c00922

“…This type of Csp 3 −Csp 2 bond formation has recently been demonstrated in radical additions to quinones through a silver-mediated deconstructive process, 29 as well as an analogous Minisci process. 30 Since the conditions for the deconstructive process that lead to an alkyl radical are somewhat acidic (as a result of the formation of hydrogen sulfate ions and carbonic acid), we hypothesized that these conditions would be amenable to Minisci-type reactions, 20 which proceed more favorably upon protonation of a heteroarene acceptor.…”

Section: Computational Study Of the Cu(i)-mediated Deconstructive C−h...mentioning

confidence: 99%

Photo- and Metal-Mediated Deconstructive Approaches to Cyclic Aliphatic Amine Diversification

Soro

¹

,

Roque

²

,

Rackl

³

et al. 2023

View full text Add to dashboard Cite

Described herein are studies toward the core modification of cyclic aliphatic amines using either a riboflavin/ photo-irradiation approach or Cu(I) and Ag(I) to mediate the process. Structural remodeling of cyclic amines is explored through oxidative C−N and C−C bond cleavage using peroxydisulfate (persulfate) as an oxidant. Ring-opening reactions to access linear aldehydes or carboxylic acids with flavin-derived photocatalysis or Cu salts, respectively, are demonstrated. A complementary ringopening process mediated by Ag(I) facilitates decarboxylative Csp 3 −Csp 2 coupling in Minisci-type reactions through a key alkyl radical intermediate. Heterocycle interconversion is demonstrated through the transformation of N-acyl cyclic amines to oxazines using Cu(II) oxidation of the alkyl radical. These transformations are investigated by computation to inform the proposed mechanistic pathways. Computational studies indicate that persulfate mediates oxidation of cyclic amines with concomitant reduction of riboflavin. Persulfate is subsequently reduced by formal hydride transfer from the reduced riboflavin catalyst. Oxidation of the cyclic aliphatic amines with a Cu(I) salt is proposed to be initiated by homolysis of the peroxy bond of persulfate followed by α-HAT from the cyclic amine and radical recombination to form an α-sulfate adduct, which is hydrolyzed to the hemiaminal. Investigation of the pathway to form oxazines indicates a kinetic preference for cyclization over more typical elimination pathways to form olefins through Cu(II) oxidation of alkyl radicals.

show abstract

“…Nevertheless, these transformations are associated with limited scopes with little diversity regarding which functionalities that can be introduced during the C−N cleavage [7c] . Difluorocarbene transfer constitutes a more recent variant of this strategy and has enabled efficient N,C ‐difunctionalizations of a wider scope of common cyclic amines (route d) [10e] . Other important advancements include the elegant silver‐mediated deconstructive fluorination by Sarpong and co‐workers, using cyclic amines as alkyl radical precursors (route e) [9c] …”

Section: Introductionmentioning

confidence: 99%

Synthesis of Complex Diarylamines through a Ring‐Opening Difunctionalization Strategy**

Linde,

Olofsson

2023

View full text Add to dashboard Cite

The diarylation and skeletal diversification of unstrained cyclic amines was exploited to expand and modify the favorable properties of this important substrate class with pivotal roles in drug discovery. Cyclic amines were employed in the synthesis of a novel class of amino‐substituted diaryliodonium salts, which were converted to highly functionalized diarylamines through an atom‐efficient one‐pot N‐arylation/ ring opening reaction with external nucleophiles. The reaction proceeds through in situ formation of a diarylammonium intermediate that undergoes a nucleophilic ring opening by cleavage of the strong C‐N bond. A wide variety of diarylamines was obtained through introduction of two different aryl groups of varied electronics, and the retained iodo‐substituent enables downfield diversifications of the products. More than 20 nucleophiles, including amines, phenols, carboxylic acids, thiols and halides, were alkylated with high functional group tolerance, and the strategy proved efficient also in in late‐stage functionalization of natural products and pharmaceuticals.

show abstract

Synthesis of Complex Diarylamines through a Ring‐Opening Difunctionalization Strategy**

Linde,

Olofsson

2023

Angewandte Chemie

0

View full text Add to dashboard Cite

The diarylation and skeletal diversification of unstrained cyclic amines was exploited to expand and modify the favorable properties of this important substrate class with pivotal roles in drug discovery. Cyclic amines were employed in the synthesis of a novel class of amino‐substituted diaryliodonium salts, which were converted to highly functionalized diarylamines through an atom‐efficient one‐pot N‐arylation/ ring opening reaction with external nucleophiles. The reaction proceeds through in situ formation of a diarylammonium intermediate that undergoes a nucleophilic ring opening by cleavage of the strong C‐N bond. A wide variety of diarylamines was obtained through introduction of two different aryl groups of varied electronics, and the retained iodo‐substituent enables downfield diversifications of the products. More than 20 nucleophiles, including amines, phenols, carboxylic acids, thiols and halides, were alkylated with high functional group tolerance, and the strategy proved efficient also in in late‐stage functionalization of natural products and pharmaceuticals.

show abstract

Deconstructive Pyridylation of Unstrained Cyclic Amines through a One-Pot Umpolung Approach

Cited by 8 publications

References 55 publications

Photo- and Metal-Mediated Deconstructive Approaches to Cyclic Aliphatic Amine Diversification

Photo- and Metal-Mediated Deconstructive Approaches to Cyclic Aliphatic Amine Diversification

Synthesis of Complex Diarylamines through a Ring‐Opening Difunctionalization Strategy**

Synthesis of Complex Diarylamines through a Ring‐Opening Difunctionalization Strategy**

Contact Info

Product

Resources

About