Monitoring Mechanistic Details in the Synthesis of Pyrimidines via Real-Time, Ultrafast Multidimensional NMR Spectroscopy

Recent years have witnessed unprecedented advances in
the development
of fast multidimensional NMR acquisition techniques. This progress
could open valuable new opportunities for the elucidation of chemical
and biochemical processes. This study demonstrates one such capability,
with the first real-time Two-dimensional (2D) dynamic analysis of
a complex organic reaction relying on unlabeled substrates. Implementing
such measurements required the development of new ultrafast 2D methods,
capable of monitoring multiple spectral regions of interest as the
reaction progressed. The alternate application of these acquisitions
in an interleaved, excitation-optimized fashion, allowed us to extract
new structural and dynamic insight concerning the reaction between
aliphatic ketones and triflic anhydride in the presence of nitriles
to yield alkylpyrimidines. Up to 2500 2D NMR data sets were thus collected
over the course of this nearly 100 min long reaction, in an approach
resembling that used in functional magnetic resonance imaging. With
the aid of these new frequency-selective low-gradient strength experiments,
supplemented by chemical shift calculations of the spectral coordinates
observed in the 2D heteronuclear correlations, previously postulated
intermediates involved in the alkylpyrimidine formation process could
be confirmed, and hitherto undetected ones were revealed. The potential
and limitations of the resulting methods are discussed.