COMBINATORIAL CHEMISTRY
250
CHIMIA 2003, 57, No. 5
Table 1. Preparation of pyrazolo[1,5a]-[1,3,5]-triazin-4-ones 8.
is critically dependent on the availability
of the necessary building blocks. As shown
in Scheme 2, we selected ethyl-2-amino
cyano acetate 13, a multifunctional central
building block, easily accessible by the
reduction of ethyl cyano-(hydroxyimino)
acetate 12 [10–12], to generate a palette of
pharmacologically relevant core structures,
such as thiazoles 15, oxazoles 20 and imi-
dazolones 24, with additional elements of
structural diversity.
Yielda/Purityb
[%]
R1
R2
H
R3
H
Products
R4R5N-
O
8a
45/76
N
NH
NH
N
N
N
H
H
8b
8c
53/95
66/82
N
NH
NH
Thus, we describe in Scheme 2 a rapid
entry into a series of polyfunctionalized
thiazoles 15, easily obtained in pure form
by simple precipitation, in good yields and
purities (Table 3) starting from ethyl-2-
amino cyano acetate 13 and isothiocyanates
14. Subsequent condensation with ethoxy-
carbonyl-isothiocyanate 2 and treatment
with sodium ethanolate in EtOH at 75 °C,
led to the corresponding fused heterocycles
of type 16 in pure form after acidification,
precipitation and filtration of the suspen-
sion (Table 3). S-alkylation of 16 with
MeI performed in acetone with Cs2CO3,
followed by chlorination with POCl3 in
toluene in the presence of DIPEAat 110 °C,
afforded the corresponding 4-chloro inter-
mediates, which underwent nucleophilic
substitution with amines 17 to furnish
compounds of type 18 in pure form (Table 4).
At this stage removal of solution-phase
excess reactants, reagents, and byproducts
is accomplished by incubation with CMR/R
resins (Complementary Molecular Reac-
tivity and Recognition resins: [13]) and fil-
tration of the reaction mixture. The CMR/R
library purification strategy is general and
highly amenable to automation.
H
H
8d
8e
84/96
80/97
OH
NH
N
H
H
N
N
N
H
8f
72/99
N
H
H
Br
Br
H
H
8g
8h
67/99
81/92
N
N
N
O
O
N
N
N
H
CO2Et
H
8i
87/94
aYields in % are based on weight of crude material and are relative to the initial loading. bHPLC
Purity of the purified material (confirmed by 1H-NMR), measured on YMC-Pack Pro C18
column (75ϫ4.6 mm) with a gradient 12% AcCN/H2O → 95% AcCN within 5.4 min; flow rate,
2.64 ml/min; UV detection at 200–300 nm.
In order to explore in depth the potential
of our building block 13 to generate highly
functionalized heterocycles libraries, we
studied the reaction of 13 with acyl chlo-
rides of type 19 under standard conditions
and subjected the corresponding amide
to acid-catalyzed cyclization (Scheme 2),
affording amino-oxazoles 20 in good over-
all yields and purities (Table 5). At this
stage, applying the previously described
process: condensation with ethoxycarbonyl-
isothiocyanate 2, and treatment with sodi-
um ethanolate led to the corresponding
fused heterocycles of type 21 (Table 5).
Finally S-alkylation of 21, followed by
chlorination and nucleophilic substitution
yielded compounds of type 22 in pure
form, using the CMR/R library purification
strategy (Table 4).
Table 2. Preparation of pyrazolo[1,5a]-[1,3,5]-triazines 11.
Yielda/Purityb
R1
R2
H
R4R5N-
R6NH-
NH2
Products
[%]
NH
11a
75/96
O
NH
H
11b
11c
80/99.5
77/95
NH2
O
NH
Me-S
CN
NH2
NH2
F
NH
Me-S
Me
CN
H
11d
11e
83/99
67/92
S
NH
NH
N
NH
N
O
Me
H
11f
67/94
O
Additionally to demonstrate the ver-
satility of our building block 13, we con-
densed 13 with isocyanates 23, and submit-
ted the corresponding intermediates to an
acid-catalyzed cyclization, allowing us to
generate imidazolones of type 24. Fused
aYields in % are based on weight of crude material and are relative to the initial loading. bHPLC
Purity of the purified material (confirmed by 1H-NMR), measured on YMC-Pack Pro C18
column (75ϫ4.6 mm) with a gradient 12% AcCN/H2O → 95% AcCN within 5.4 min; flow rate,
2.64 ml/min; UV detection at 200–300 nm.