Synthesis of Labeled Caffeine - Caffeine: Chemistry, Analysis, Function and Effects - page 73

synthesis of caffeine from labeled building blocks and partial synthesis
by alkylation of an appropriate xanthine derivative with a labeled methyl
group.

d n 0 t 2 n g | 2

5.2.1 Synthesis of Labeled Caffeine by Hydrogen Exchange
Under specific conditions, caffeine undergoes hydrogen exchange: one or
several hydrogen atoms in the molecule are exchanged for deuterium or
tritium. A labile hydrogen atom (H-8, on the imidazole ring) is easily
exchanged for tritium from [ 3 H 2 ]O. The exchange of non-labile hydrogen
atoms with hydrogen isotopes from deuterated or tritiated water, or with
deuterium or tritium gas requires a metal catalyst.
The regioselectivity of the labeled atom introduction and the isotope
enrichment ratio depend on the procedure used and especially on the nature of
the metal catalyst.
This labeling procedure sounds attractive because caffeine is the starting
material, and so long multistep synthesis is avoided. Quantitative yields are
usually high and isotope composition is satisfactory.

5.2.2 Synthesis of Labeled Caffeine through Total Synthesis
This method is used when the molecule is to be labeled at the xanthine ring
skeleton. In this case, the introduced isotopes are not subject to exchange in
aqueous medium (as for H-8 hydrogen) or to metabolic elimination (such as
methyl groups on nitrogen atoms).
Starting from the appropriate labeled building block, this method allows the
regioselective labeling of any atom on the xanthine ring.
The synthetic procedure is based on the historical Traube synthesis (Traube
1900). Fortunately, caffeine can be prepared with basic starting compounds
such as urea, formic acid or formamide labeled with various isotopes and
which are commercially available.
Tedious multistep synthesis is the major drawback of this procedure,
especially when the isotopes are introduced at the earlier step, leading to some
extensive loss of labeled material.

5.2.3 Synthesis of Labeled Caffeine by Partial Synthesis with a
Xanthine Derivative
Labeled caffeine is readily prepared from xanthine or its mono- or dimethyl-
derivatives by alkylation of the unsubstituted nitrogen atoms with an
appropriate labeled methylating agent. Thus, unsubstituted nitrogen atoms
of the xanthine derivative are methylated to afford caffeine as the sole product.
The number and position of labeled methyl groups depend on the initial
xanthine derivative.