818
J. Comb. Chem. 2010, 12, 818–821
Our synthesis program started from the amide 11 (Scheme
Synthesis of a Solid-Phase Amino
Imidazotriazine Library via Palladium
Catalyzed Direct Arylation
1), which we envisaged could be directly transformed into a
resin-bound amine 12 by adaptating recently published
solution-phase chemistry.13 The starting heterocyclic amide
11 can be synthesized in three steps from the imidazole 98
or in four steps from the triazine 105,14 (Scheme 1).
Simon Maechling,* James Good, and Stephen D. Lindell*
Bayer CropScience GmbH, Werk Ho¨chst, G836, D-65926,
Frankfurt am Main, Germany
Four simple alkyamines were chosen for the first diversity
point R1 (Figure 2). These amines were attached to a 2-(4-
formyl-3-methoxyphenoxy)ethyl (FMPE) polystyrene resin
by reductive amination to give resins 14 (contained in 20
MicroKans) (Scheme 2).15 The substitution reaction to attach
the heterocycle to the resin was carried out by treating the
resins 14 and the heterocyclic amide 11 in DMF with DBU,
followed by addition of PyBOP and heating to 60 °C for
66 h. Filtration and thorough washing of the MicroKans
afforded the resin-bound intermediates 16. Cleavage of trial
MicroKans at this stage afforded good yields of products 4
which are also of interest as potential kinase inhibitors.
ReceiVed August 5, 2010
Heteroarenes, including imidazoles and triazines, are
important structural units frequently found in natural prod-
ucts,1 pharmaceuticals,2 and agrochemicals.3 The biological
importance and structural variation of heterocyclic derivatives
provide a significant synthetic challenge, particularly when
concerned with efficiently synthesizing large numbers of
discrete analogues. Modern combinatorial chemistry plays
a key role in the search for lead structures displaying
biological activity and represents a powerful methodology
for the synthesis of compound libraries for biological
evaluation.4 Considering the frequent occurrence of hetero-
cyclic frameworks in known pharmaceutical and agrochemi-
cal biologically active entities, they make an attractive target
for diversification utilizing combinatorial synthetic ap-
proaches. Of particular importance to lead discovery is the
incorporation of novel heterocyclic cores into library design
and production. A good example is the imidazo[2,1-f]-
[1,2,4]triazine core 1 (Figure 1), which represents a currently
little known heterocylic system but which clearly has an
interesting biological potential as illustrated by the adenosine
deaminase inhibitor 5,5 the antiviral agent 6,6 the GABA
agonist 7,7 and the tyrosine kinase inhibitor 8.8
In the current work, we focused our attention on the use of
the 7-amino-imidazo[2,1-f][1,2,4]triazine (2) (Figure 1) as an
attractive core structure that we envisaged could be derivatized
to give a protein kinase targeted library of general structure 3.9
For the production of the library, we planned to use a Heck-
like direct arylation reaction to functionalize the C-3 position
(Scheme 1). The direct arylation reaction of imidazotriazines7
and of many other heterocyclic systems10 has been previously
reported but has, to the best of our knowledge, not been used
to functionalize resin bound imidazole based heterocycles. This
reaction has some advantages over traditional cross-coupling
methods (e.g., Stille, Suzuki, and Negishi),11 in that there is no
need to synthesize heterocyclic halides or organometallic
intermediates (B, Sn, Zn). In addition, undesired side reactions
such as protodehalogenation and protodemetalation do not af-
fect the purity of the final products, thus simplifying or even
avoiding the need for postsynthesis purification. This paper
discloses the synthesis and characterization of a sample solid-
phase library of 20 compounds prepared using IRORI MicroKan
technology.12
Five simple aryl bromides were chosen for the second
diversity point R2 (Figure 2). The key palladium catalyzed
arylation coupling step to generate intermediate 17 on the
solid phase (Scheme 2) was performed under a nitrogen-
atmosphere with reagent grade solvents. No extensive drying
or degassing protocols were necessary. A 5-fold excess of
aryl halide and base was used to drive the reaction to
completion. Since workup and purification involved a simple
filtration, this did not cause any postsynthesis purification
problems. Following arylation the products were cleaved
from the resin using 50% TFA in CH2Cl2 to afford the
products 3 listed in Table 1 and shown in Figure 3. The
products were isolated in modest to good yield and in high
purity demonstrating an advantage of this approach when
compared to conventional coupling methodologies. The
1
purities of the compounds were measured using H NMR
and both evaporative light scattering (ELS) and diode array
detectors (DAD, 220 and 260 nm). There was a good overall
1
agreement between compound purities determined by H
1
NMR, ELS, and UV at 260 nm. The H NMR and mass
spectra for all compounds were entirely in agreement with
the assigned structures (see Supporting Information).
The electron-deficient aryl halide 15{1} reacted as a very
efficient electrophile in the arylation reaction affording
products 3{1,1}, 3{2,1}, 3{3,1}, and 3{4,1} in excellent
purity >97% as determined by 1H NMR (Table 1, entries 1,
6, 11, 16). The deactivated aryl halides 15{2} and 15{4}
also gave the products in excellent purity >95% (Table 1).
The direct arylation reaction also proved highly successful
with the relatively sterically hindered substrate 15{3},
affording 3{1,3}, 3{2,3}, 3{3,3}, 3{4,3} (Table 1, entries
3, 8, 13, 18) although some nonarylated product could be
detected after cleavage (<5%). Utilization of the relatively
more electron rich aryl halide 15{5} afforded the products
with the lowest average purity in the test subset, although
even here the purity was mostly good, laying at around 90%
* To whom correspondence should be addressed. E-mail: simon.maechling@
bayercropscience.com (S.M.) or stephen.lindell@bayercropscience.com
(S.D.L.).
10.1021/cc1001617 2010 American Chemical Society
Published on Web 09/29/2010
Maechling, Simon
