inspired by these unique features of xanthine to design
and identify fluorescent xanthine-based kinase inhibitors.
The classical condensation route appeared unsuitable for
the synthesis of diverse derivatives because the preparation
requires many steps and often provides low yields.6 To
facilitate the exploration of N7- and C8-substituents, we
identified theophylline (ca. $75/500 g, TCI) as a convenient
starting point. Our synthetic strategy toward the target
compounds was based on a versatile combination of regi-
oselective N7-arylation and/or direct C8-arylation (Figure
2).
Table 1. Optimization of the Coupling of Theophylline (1) with
4-Methoxyphenylboronic Acid (2)a
base
(equiv)
temp,
°C
yield,b
%
entry
solvent
1
2
3
4
5
TMEDA (2)
TMEDA (2)
TMEDA (2)
Et3N (2)
Et3N (2)
K2CO3 (2)
-
pyridine (2)
pyridine (2)
pyridine (2)
pyridine (2)
pyridine (2)
lutidine (2)
MeOH/H2O
MeOH
MeOH/H2O
DMF
MeOH/H2O
DMF
MeOH
CH2Cl2
DMF
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
rt
rt
70
rt
rt
rt
rt
rt
rt
3
trace
10
10
15
trace
9
23
15
22
38
60
35
6
7
8c
9
10
11
12d
13d
rt
Figure 2. Strategy to xanthine derivatives from arrays of A and B
rings.
40
40
40
a Reactions were carried out with Cu(OAc)2 (2 equiv), theophylline (1
equiv), and 4-methoxyphenylboronic acid (1.5 equiv) for 24 h. b Yield of
isolated product. c Molecular sieves (4 Å) added. Reaction was carried out
for 3 days. d Theophylline (2 equiv) and 4-methoxyphenylboronic acid (1
equiv). Yield of isolated products was calculated from the amount of boronic
acid.DMF)N,N-dimethylformamide,TMEDA)N,N,N′,N′-tetramethylethylenediamine.
Copper-mediated C-N coupling reactions of NH func-
tions with arylboronic acids have been developed as
powerful synthetic methodology.7 On the basis of pub-
lished procedures for the N-arylation of general nucleo-
bases,8 theophylline could be arylated at the N7 position
selectively but in low yield (Table 1, entries 1-6). These
disappointing results prompted us to search for other
reaction conditions. Fortunately, when pyridine or 2,6-
lutidine was used as the base, the yield of the product
increased significantly. After screening a variety of bases,
solvents, and temperatures (Table 2, entries 1-13), the
best result was obtained in CH2Cl2 at 40 °C for 24 h with
2 equiv of pyridine as the base in the presence of
copper(II) acetate (Table 1, entry 12). Both electron-
donating and electron-withdrawing substituents on the aryl
boronic acids were well tolerated.
Having successfully installed the N7-aryl ring onto the
theophylline, we next turned to direct C8 arylation. We intended
to build the C8-(hetero)aryl ring by means of the copper-
catalyzed C-H bond activation path. Whereas the coupling of
N7-methyl or benzyl xanthine with aryl bromide under com-
parable reaction conditions yielded the desired products in high
yields, attempts to couple the N7-aryl xanthine such as 3 with
aryl bromide 4 were unsuccessful, affording only unreacted
materials. It seemed that the replacement of the N7 methyl with
an aryl group influences the electronics of the xanthine core
leading to a change in the reactivity for C-H arylation. To
circumvent these synthetic challenges, we investigated more
effective reaction conditions for the direct C-H arylation.9
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