Tetrahedron Letters
Rapid construction of imidazopyridines from
ortho-haloaminopyridines
a
a
b
Chaomin Li a, , Lily Chen , Dietrich Steinhuebel , Andrew Goodman
⇑
a Department of Process and Analytical Chemistry, Merck Research Laboratories, Boston, MA 02115, United States
b Department of Process and Analytical Chemistry, Merck Research Laboratories, Rahway, NJ 07065, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
A practical strategy for the preparation of imidazopyridine derivatives from ortho-haloaminopyridines
utilizing a two-step C–N coupling/cyclization reaction sequence has been developed. This procedure pro-
vides rapid and efficient access to many medicinally interesting imidazopyridine compounds and related
imidazopyrazine/purine heterocycles.
Received 16 March 2016
Revised 21 April 2016
Accepted 27 April 2016
Available online 9 May 2016
Ó 2016 Elsevier Ltd. All rights reserved.
Keywords:
Imidazopyridine
Ortho-haloaminopyridine
C–N coupling
Imidazopyrazine
Purine
Imidazopyridine1 derivatives are of great importance for their
diverse biological properties, which may be related to their struc-
tural similarity to purines and indole/azaindole derivatives, the
important building blocks of DNA/RNA and the basic heterocyclic
structure found in numerous alkaloids. Many imidazopyridine
derivatives possess interesting biological activities and therefore
are used as antibacterial2, antivirus3, anti-inflammatory4, and
antitumor agents.5 They have also found utility as herbicides and
fungicides.6
During lead optimization of a drug discovery program, a novel
analog containing an imidazopyridine core was identified and
found to significantly improve the in vitro potency as well as the
in vivo efficacy compared with the original purine leads. Our initial
imidazopyridine alkylation approach resulted in very low yield
(ꢀ15%) of desired product due to poor N3/N1 selectivity. Alterna-
tive route from readily available aminopyridine was then devised
which utilized ortho nitration as the first transformation.7
Although this route selectively introduced alkyl group to the N3
nitrogen, it was inefficient for SAR studies because of the large
number of steps (6 steps) required to build up the imidazole ring.
Recognizing the limitations of this route, we explored a concep-
tively more efficient C–N coupling route (Scheme 1). Herein we
report the optimization and scope of the rapid construction of
imidazopyridines via the C–N coupling of alkyl amine derivatives
with ortho-haloaminopyridines8 followed by ring closure.
Although significant advances in the field of C–N coupling of
amines with aromatic halides have been reported9, there are few
reports of C–N couplings of 2-haloaniline or ortho-haloaminopy-
ridines10 with amine derivatives, which was required for our
method. Copper catalyzed C–N couplings of 2-iodoanilines with
primary amines have been reported with limited substrate scope
and success.11 In addition to SNAr12 or harsh copper catalyzed con-
ditions (200 °C, ꢀ10% yield)13 for introducing an alkylamino group
ortho to a NH2 on pyridines, the palladium catalyzed C–N cou-
plings of ortho-haloaminopyridine with alkylamines has been
reported in two cases.14 In the first case14a, a Pd/BINAP system
was used to affect the coupling of 3-bromo-4-aminopyridine in
low yield (ꢀ14%). Of most relevance to the present disclosure,
Minatti14b and coworkers recently reported
a
BrettPhos
precatalyst/LiHMDS conditions for the amination of 2-
aminopyridine scaffolds with synthetically useful yields.
We began our investigation by screening conditions for C–N
coupling of 4-amino-3-bromopyridine with benzylamine (Table 1).
The best catalyst and base were BrettPhos and LiHMDS as shown in
entry 1 (82% yield). Alternative catalysts (such as tBuXPhos, XPhos,
RuPhos, or XantPhos) did not afford the desired product in useful
yield (Table 1, entry 4–8). Surprisingly, BrettPhos G1 precatalyst
outperformed BrettPhos G3 precatalyst (45% yield, Table 1, entry
2) and Pd(OAc)2/BrettPhos (12% yield, Table 1, entry 3). The choice
of LiHMDS as base15 was found to be critical for achieving high
⇑
Corresponding author.
0040-4039/Ó 2016 Elsevier Ltd. All rights reserved.