Metal Free Access to Polysubstituted Pyrimidines via Nitrile Activation and [2+2+2] Cycloaddition

Abstract

Tf2O mediated intermolecular / intramolecular [2+2+2] cycloaddition between alkynes and nitriles has been developed for efficient construction of polysubstituted pyrimidines and bicyclopyrimidines. In presence of Tf2O, aza‐allene species were generated in situ through nitrile activation and subsequently participated in the [2+2+2] cycloaddition, which was fully supported by deuteration experiments. The reaction had good substrate extensibility with moderate to excellent yield including trimethylsilylalkynes. The method was utilized as a synthetic tool in the preparation of a luminescent metal complex.

Recent Applications of Trifluoromethanesulfonic Anhydride in Organic Synthesis

“…Additionally, Liu, Wu and co‐workers disclosed a Tf 2 O mediated intermolecular/intramolecular [2+2+2] cycloaddition between alkynes and nitriles towards the synthesis of polysubstituted pyrimidines and bicyclopyrimidines (Scheme 34). [57] Detailed deuteration experiments and competing reactions confirmed that the nitriles were initially activated by Tf 2 O into aza‐allene species and then participated in the [2+2+2] cycloaddition with alkynes. This protocol exhibited a broad substrate scope and good functional group tolerance, giving rise to various pyrimidines 162 and 164 in good yields.…”

An Accesss to 4,5,6-Trisubstituted Pyrimidines from 2H-Azirines and α-Isocyanoacetates or α-Isocyanoacetamides Enabled by 1,3-Dipolar [3 + 2] Cycloaddition/Ring-Expanding/Oxidative Aromatization Process

“…Recently, by exploiting the in situ trapping of active aza-allene species obtained from nitriles in the presence of Tf 2 O, Wu's group has demonstrated a formal [2 + 2 + 2] cyclization reaction for building such nitrogen heterocycles with alkyne reagents (Scheme 1c). 8 Subsequently, Levin's group developed a mild, transitionmetal-free methodology toward the synthesis of mono-or multisubstituted pyrimidines from the reaction between pyrazoles and diazirines by a ring expansion process (Scheme 1d). 9 In 2023, Orru's group successfully utilized isocyanides, diazo compounds, and amidines as substances to construct pyrimidines using an Fe catalyst as well (Scheme 1e).…”

“…are serious limitations of these protocols in the mentioned literature. Recently, by exploiting the in situ trapping of active aza-allene species obtained from nitriles in the presence of Tf 2 O, Wu’s group has demonstrated a formal [2 + 2 + 2] cyclization reaction for building such nitrogen heterocycles with alkyne reagents (Scheme c) . Subsequently, Levin’s group developed a mild, transition-metal-free methodology toward the synthesis of mono- or multisubstituted pyrimidines from the reaction between pyrazoles and diazirines by a ring expansion process (Scheme d) .…”