Synthesis of disubstituted imidazo[4,5-b]pyridin-2-ones

Article abstract of DOI:10.1021/jo048887v

Regioselective palladium-catalyzed amination of 2-chloro-3-iodopyridine followed by a subsequent palladium-catalyzed amination leads to 2,3-diaminopyridines. Treatment with triphosgene affords highly functionalized unsymmetrical imidazo [4,5-b] pyridin-2-

Full text of DOI:10.1021/jo048887v

plants.12 Unsubstituted imidazo[4,5-b]pyridin-2-ones of
type 1a are typically prepared by the reaction of 2,3-
diaminopyridines with a variety of acylating reagents13,14
and often serve as precursors to imidazo[4,5-b]pyridines
2 and 3. Preparation of 1,3-disubstituted imidazo[4,5-b]-
pyridin-2-ones (1b) via the selective functionalization of
either nitrogen atom of 2,3-diaminopyridine or 1a is
difficult and often requires protecting group stategies.14
While access to substituted imidazo[4,5-b]pyridin-2-ones
(1b) beginning with 2-chloro-3-nitropyridine has been
described, the overall sequence is limited in scope,
requires harsh reaction conditions leading to unstable
intermediates, and provides the desired products in low
overall yield.7,8 To fully define biological profiles, strate-
gies which give rapid access to highly functionalized
imidazo[4,5-b]pyridin-2-ones not obtainable through cur-
rent synthetic methods are important synthetic tools. In
this Note, we wish to report a general synthesis of
symmetrically and unsymmetrically 1,3-disubstituted
imidazo[4,5-b]pyridin-2-ones 1b through palladium-
catalyzed cross coupling.
Syn th esis of Disu bstitu ted
Im id a zo[4,5-b]p yr id in -2-on es
J effrey T. Kuethe,* Audrey Wong, and Ian W. Davies
Department of Process Research, Merck & Co., Inc.,
P.O. Box 2000, Rahway, New J ersey 07065
jeffrey_kuethe@merck.com
Received J uly 1, 2004
Abstr a ct: Regioselective palladium-catalyzed amination of
2-chloro-3-iodopyridine followed by a subsequent palladium-
catalyzed amination leads to 2,3-diaminopyridines. Treat-
ment with triphosgene affords highly functionalized unsym-
metrical imidazo[4,5-b]pyridin-2-ones in just three synthetic
steps. A two-step synthesis of pseudosymmetrically disub-
stituted imidazo[4,5-b]pyridin-2-ones, 1,4-disubstituted py-
rido[2,3-b]pyrazinediones, and 1,3-disubstituted thiadiazolo-
[3,4-b]pyridin-2-ones is also described.
The 1,3-dihydro-imidazo[4,5-b]pyridin-2-one ring sys-
tem (1) and related imidazo[4,5-b]pyridines (2, 3) repre-
sent the core skeletons of a pharmaceutically important
class of heterocyclic compounds possessing a range of
biological activities.1-5 Compounds within the imidazo-
[4,5-b]pyridin-2-one class (1) have been shown by Merck
to be nonsteroidal antiinflammatory and analgesic agents,6
and by others to possess antidepressant,7 antiphlogistic,8
cardiotonic,9 hypotensive and antiarrhythmic,10 and an-
tisecretory activity.11 In addition, certain members of this
class have post-emergence applications on broad-leaved
Aminopyridine derivatives are important synthetic
intermediates that have been used as acyl transfer
reagents,15 ligands in inorganic and organometallic chem-
istry,16 and fluorescent dyes.17 Aminopyridines have also
received a considerable amount of attention due to their
presence in biologically active pharmaceuticals and many
natural products.18 Recent advances by Buchwald,19 Maes
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10.1021/jo048887v CCC: $27.50 © 2004 American Chemical Society
Published on Web 09/25/2004
7752
J . Org. Chem. 2004, 69, 7752-7754

TABLE 1. P r ep a r a tion of Un sym m etr ica l
Im id a zo[4,5-b]p yr id in e-2-on es
SCHEME 1
and Dommisse,20 and J i21 have allowed for the chemo-
and regioselective palladium-catalyzed aminations of
dihalopyridines which avoids the harsh reaction condi-
tions often associated with modest yielding aromatic
substitutions of activated pyridine substrates.22 Our
approach to 1,3-disubstituted imidazo[4,5-b]pyridin-2-
ones 1b was inspired by these advances and is outlined
in Scheme 1. Reaction of 2-chloro-3-iodopyridine 423 (1.0
equiv) and aniline (0.95 equiv) in the presence of pal-
ladium acetate (3 mol %) and BINAP [2,2′-bis(diphen-
ylphosphino)-1,1′-binaphthyl] (3 mol %) in refluxing
toluene employing cesium carbonate (5 equiv)20 and
catalytic NEt324 as the base gave aminopyridine 5 in 85%
isolated yield. The molar ratio of 4 to aniline was found
to be crucial for chemoselective substitution of the iodide.
An excess of aniline often led to increased amounts of
diaminopyridines (vida infra). The use of alkylamines did
not affect the chemo- or regioselectivity of the reaction
and afforded the monoaminated products in good yield
(Table 1). Coupling of 5 with 3,4-(methylenedioxy)aniline
in the presence of Pd2(dba)3 (1.5 mol %) and BINAP (4.5
mol %) employing sodium tert-butoxide19 as the base gave
diaminopyridine 6 in 80% isolated yield. Subsequent
reaction with triphosgene/NEt3 in tetrahydrofuran gave
the unsymmetrically substituted 1,3-dihydro-3-[3,4-(me-
thylenedioxy)phenyl]-1-phenyl-imidazo[4,5-b]pyridin-2-
one 7 in near quantitative yield. The three-step reaction
sequence proved to be general and afforded a diverse
array of unsymmetrically substituted imidazo[4,5-b]-
pyridin-2-ones bearing a variety of functional groups
(Table 1). In most cases, the aminochloropyridines and
(20) (a) Maes, B. U. W.; Loones, K. T. J .; J onckers, T. H. M.; Lemie´re,
G. L. F.; Dommisse, R. A. Synlett 2002, 1995. (b) J onckers, T. H. M.;
Maes, B. U. W.; Lemie´re, G. L. F.; Dommisse, R. A. Tetrahedron 2001,
57, 7027.
(21) J i, J .; Bunnelle, W. H. Org. Lett. 2003, 5, 4611.
(22) (a) Vorbruggen, H. Advances in Heterocyclic Chemistry; Aca-
demic Press: San Diego, CA, 1990; Vol. 49, pp 117-192. (b) Gupton,
J . T.; Idoux, J . P.; Baker, G.; Colon, C.; Crews, A. D.; J urss, C. D.;
Rampi, R. C. J . Org. Chem. 1983, 48, 2933. (c) Pedersen, E. B.; Carlsen,
D. Synthesis 1978, 844. (d) Patel, K. M.; Sparrow, J . T. Synth.
Commun. 1979, 9, 251. (e) Vorbruggen, H. Synthesis 1973, 301.
(23) Sakamoto, T.; Kondo, Y.; Yamanaka, H. Chem. Pharm. Bull.
1985, 33, 4764. For an improved procedure describing the preparation
of 4 see the Supporting Information.
(24) The use of triethylamine has been shown to provide significant
rate enhancement in palladium-catalyzed aminations of aryl iodides
when cesium carbonate is employed as the base. For a leading reference
see: Ali, M. H.; Buchwald, S. L. J . Org. Chem. 2001, 66, 2560.
diaminopyridine intermediates could be either isolated
by direct crystallization from the crude reaction mixture
J . Org. Chem, Vol. 69, No. 22, 2004 7753

TABLE 2. P r ep a r a tion of Sym m etr ica l
Im id a zo[4,5-b]p yr id in -2-on es
SCHEME 2
or were used directly in subsequent transformations
without further purification.25
Having established a three-step protocol for the prepa-
ration of unsymmetrically substituted products, our
attention turned to the preparation of pseudosymmetri-
cally disubstituted imidazo[4,5-b]pyridin-2-ones. For ex-
ample, reaction of 4 with aniline (2.5 equiv) in the
presence of palladium acetate (3 mol %)/BINAP (3 mol
%) in refluxing toluene with 5 equiv of Cs2CO3 as the base
gave diaminopyridine 28 as the sole reaction product that
could be crystallized from the crude reaction mixture in
83% isolated yield (Scheme 2). Cyclization of 28 with
triphosgene/NEt3 afforded 29 in 98% yield. In similar
fashion, reaction of 4 with an excess of 2,5-difluoroaniline,
3-trifluoromethylaniline, and 1-naphthylamine yielded
diaminopyridines 30-32 in high yield (Table 2). Cycliza-
tion with triphosgene gave the symmetrically disubsti-
tuted imidazo[4,5-b]pyridin-2-ones 33-35 in just two
synthetic steps and excellent overall yield (Scheme 2).
Finally, access to other novel heterocyclic ring systems
through reaction of 28 and 31 with oxalyl chloride or
thionyl chloride was demonstrated. For example, reaction
of 28 or 31 with oxalyl chloride afforded the 1,4-disub-
stituted pyrido[2,3-b]pyrazinediones 36 and 37 in 95%
and 97% yields, respectively.26 Reaction of 28 with thionyl
chloride furnished 1,3-diphenylthiadiazolo[3,4-b]pyridin-
2-one 38 in 89% yield.
disubstituted-1,3-dihydro-imidazo[4,5-b]pyridin-2-ones
through a sequential palladium-catalyzed coupling pro-
tocol has been demonstrated. The reaction conditions are
mild and tolerant of a wide range of functional groups.
This method allows for the preparation of novel hetero-
cycles that are pharmaceutically interesting in two or
three synthetic steps which are not accessible through
current synthetic methods.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and compound characterization for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
J O048887V
(26) Unsubstituted pyrido[2,3-b]pyrazinediones have been shown to
possess antagonistic activity at the glycine site on the N-methyl-D-
aspartate (NMDA) receptor which has been implicated in several
neurodegenerative disorders such as Alzheimer’s diesease, epilepsy,
and stroke. For a leading reference, see: Cugola, A.; Donati, D.;
Guarneri, M.; Micheli, F.; Missio, A.; Pecunioso, A.; Reggiani, A.;
Tarzia, G.; Zanirato, V. Bioorg., Med. Chem. Lett. 1996, 6, 2749 and
references therein.
In summary, a general, high-yielding method for the
preparation of symmetrically and unsymmetrically 1,3-
(25) In certain cases where the reaction product was used crude,
minor amounts of unreacted starting materials were present. The
presence of these impurities had no detrimental affect on the outcome
of subsequent transformations.
7754 J . Org. Chem., Vol. 69, No. 22, 2004