TY - JOUR

T1 - Synthesis and a Kinetic Study of the Reactivity of 1-Amino-7,7-dimethylbicyclo[2.2.1]heptan-2-one in Alkylation Reactions with Structurally Similar Amines

AU - Tishchenko, Serafim

AU - Sokolova, Anastasiya S.

AU - Arbuzova, Margarita A.

AU - Selyutina, Olga Yu

AU - Tsypyshev, Dmitry O.

AU - Yarovaya, Olga I.

AU - Arkhipov, Sergey G.

AU - Salakhutdinov, Nariman F.

N1 - The authors would like to acknowledge the Multi-Access Chemical Research Centre SB RAS for spectral and analytical measurements. This work was supported by grant No. 24–73–00137 from the Russian Science Foundation.

PY - 2025/5/23

Y1 - 2025/5/23

N2 - Amine-containing natural products have garnered much attention in synthetic chemistry owing to their potential as starting points in medicinal chemistry. In this study, we present an improved method for the synthesis of (1S,4R)-1-amino-7,7-dimethylbicyclo[2.2.1]heptan-2-one (1) and conduct a comparative analysis of its reactivity in alkylation reactions with structurally related amines. The synthetic route involved the activation of the carboxylic group using an acid chloride for acyl azide synthesis, isolation of the acyl azide in its pure form, and subsequent rearrangement via reflux in toluene, enabling the preparation of target amine 1. The reactivity of amine 1 was investigated in comparison with a series of other amines in alkylation reactions. The reaction of each amine with methyl iodide resulted in nonspecific alkylation, giving rise to mono- and dialkylated products. Reactions with allyl and benzyl bromide yielded only monoalkylated products. Kinetic analysis revealed that the alkylation of each amine with MeI and allyl bromide proceeded via the SN2 mechanism. In contrast, amine 1 reacted with benzyl bromide via the SN1 mechanism, whereas the other amines followed the SN2 pathway. Calculations of nucleophilicity parameters also showed that amine 1 manifests reduced nucleophilicity compared to the other studied amines.

AB - Amine-containing natural products have garnered much attention in synthetic chemistry owing to their potential as starting points in medicinal chemistry. In this study, we present an improved method for the synthesis of (1S,4R)-1-amino-7,7-dimethylbicyclo[2.2.1]heptan-2-one (1) and conduct a comparative analysis of its reactivity in alkylation reactions with structurally related amines. The synthetic route involved the activation of the carboxylic group using an acid chloride for acyl azide synthesis, isolation of the acyl azide in its pure form, and subsequent rearrangement via reflux in toluene, enabling the preparation of target amine 1. The reactivity of amine 1 was investigated in comparison with a series of other amines in alkylation reactions. The reaction of each amine with methyl iodide resulted in nonspecific alkylation, giving rise to mono- and dialkylated products. Reactions with allyl and benzyl bromide yielded only monoalkylated products. Kinetic analysis revealed that the alkylation of each amine with MeI and allyl bromide proceeded via the SN2 mechanism. In contrast, amine 1 reacted with benzyl bromide via the SN1 mechanism, whereas the other amines followed the SN2 pathway. Calculations of nucleophilicity parameters also showed that amine 1 manifests reduced nucleophilicity compared to the other studied amines.

KW - Alkylation reactions kinetics

KW - Amine-containing bicyclic monoterpenoid

KW - NMR

KW - Nucleophilicity

UR - https://www.mendeley.com/catalogue/f7548922-d3d3-37f4-9b30-1b2171f50cf9/

UR - https://www.scopus.com/record/display.uri?eid=2-s2.0-105006633025&origin=inward&txGid=8d21e3559a18d2fa13af7798e3a4e7ea

U2 - 10.1002/slct.202405689

DO - 10.1002/slct.202405689

M3 - Article

VL - 10

JO - ChemistrySelect

JF - ChemistrySelect

SN - 2365-6549

IS - 20

M1 - e05689

ER -