Synthesis of Labeled Caffeine - Caffeine: Chemistry, Analysis, Function and Effects - page 74

Methyl iodide labeled with various isotopes of carbon or hydrogen is one of
the most convenient methylating agents. Furthermore, xanthine, methyl-
xanthine and dimethylxanthine are commercially available and their prepara-
tion is well documented. Consequently, direct methylation of the appropriate
xanthine derivative with labeled methyl iodide is obviously the most direct
procedure for the preparation of labeled caffeine. So far this method, which
allows for the synthesis of labeled caffeine in a single step, has been the most
investigated.
The methylation of unsubstituted nitrogen atoms is carried out in a polar
solvent in the presence of a base at room temperature or with moderate
heating.
The isotopic composition of the labeled caffeine depends only on the
isotopic purity of the labeled methylating agent.
The alkylation rate with labeled methylating agents of unsubstituted nitrogen
in the xanthine ring has been poorly investigated. Nevertheless, it has been
reported that N-3 is more reactive than N-1 (Balssa and Bonnaire 2007) and that
the methylation rate of N-7 is superior to N-1 (Pierce et al 1984).

d n 0 t 2 n g | 2

5.3 Syntheses of Labeled Caffeine

5.3.1 Synthesis of [ 15 N 2 ]Caffeine
[ 15 N 2 ]caffeine was prepared from [ 15 N 2 ]urea by total synthesis (Kenani et al
1995). [ 15 N 2 ]urea (1) was converted into [1,3- 15 N 2 ]-5,6-diaminouracil (4) in
three steps. The imidazole ring was then closed by the action of formamide to
give [1,3- 15 N 2 ]xanthine (5).

Scheme 5.1 Synthesis of [1,3- 15 N 2 ]caffeine. [1,3- 15 N 2 ]Caffeine was prepared from

[ 15 N 2 ]urea by total synthesis in five steps. [1,3- 15 N 2 ]caffeine (6) was
obtained by methylation of the intermediate [1,3- 15 N 2 ]xanthine (5) with
dimethylsulfate. Labeled atoms are indicated by an asterisk.