ACS Combinatorial Science
Letter
of triphenylphosphine oxide byproduct would complicate the
purification of final products, depending on their polarity. Thus,
we turned to a combination of bidendate ligand Xantphos and
Cs2CO3 in dioxane, a system previously reported for the
ureidation of 2-chloropyridine.23 Table 1 illustrates the scope
for this chemistry. Notably, free alkylamines or hydrochlorides
(entries 3, 6, and 7) can be used indistinctly although increasing
the bulk around amino group led to less efficient couplings
(entry 8). Potential palladium coordinating groups such as
nitrile or sulfide were also tolerated (entries 6 and 11), whereas
a secondary sulfonamide motif, deprotonated under basic
conditions, possibly interferes with the ureidation process by
competing for metal ligation (entry 12).24 Primary anilines also
delivered the cyclized products 10 m-o (entries 13−15),
although reactions with ortho-substituted or moderately
electron-deficient anilines proved sluggish, affording 10n−o
in modest yield. The major side-product isolated from crude
mixtures turned out to be the homodimer 9, likely arising from
first disproportionation of intermediate N-arylurea to 3-N-
methylamino-2-bromopyridine 6, which underwent Pd-cata-
lyzed homocoupling (see Scheme 3).25
Those results suggest that the ureidation process was highly
sensitive to both steric and electronic effects. We next turned
our attention to the imidazo[4,5-c]pyridine-2-one series.
Reported intermolecular couplings between 4-chloropyridine
and ureas proved low yielding.23,26 We anticipated the
intramolecular palladium-catalyzed ureidation of 4 to be less
favorable than for 3. First, initial oxidative addition to Pd0 is
slower for C−Cl bond than for C−Br bond. More importantly,
reductive elimination, reported to be the rate-determining step
in the ureidation process,25 proceeds probably faster from 2-
pyridylpalladium amido complex relative to 4-pyridylpalladium
amido complex because of a stronger inductive effect of the
pyridyl nitrogen. In addition, the base-promoted urea
disproportionation side-reaction observed by us and others
for the intramolecular Pd catalyzed C−N bond formation was
pronounced under more basic conditions, at higher temper-
atures and under prolonged heating.15,23 We thus considered
limiting the temperature to 80−85 °C and using the system
described by McLaughlin: a combination of the mild base
NaHCO3, cheap bidendate phosphine ligand 1,4-bis-
(diphenylphosphino)butane (dppb) and Pd(OAc)2 as a
palladium source.15 To perform a rapid solvent screen, 4 was
first reacted with 3-methylbutylamine: iPrOH afforded both a
cleaner reaction profile and higher conversion than dioxane or
toluene (see Table 2, entry 1, footnote e) and was therefore
selected for the parallel synthesis of substituted imidazo[4,5-
c]pyridine-2-ones. Table 2 illustrates the scope for this
chemistry. A variety of functionalized primary alkylamines
underwent smooth coupling via their corresponding urea, even
at relatively low temperature. Amine hydrochlorides were also
tolerated, but required the use of the stronger base K2CO3
(entry 9, footnote d). In addition, volatile amines were first
converted into intermediate urea at room temperature and then
cyclized at 80−85 °C (entries 4 and 6). A limitation of the
method, already mentioned is the previous series, is that
sterically hindered alkylamine (entry 9) and electron-deficient
aryl and heteroarylamine (entry 11) failed to deliver imidazo-
[4,5-c]pyridine-2-ones 11i and k in consistent yield.27 Notably,
we assume that the unfavorable electron-deficient character of
the urea moiety, especially for anilines bearing electron-
withdrawing groups and heteroarylamines, does prevent the
key reductive elimination step of the palladium catalytic cycle,
leading to extensive urea cleavage side-products.28
In summary, we developed an access to substituted
imidazo[4,5-b]pyridine-2-one and relatively unexplored18,29,30
imidazo[4,5-c]pyridine-2-one ring systems that is both facile an
amenable to parallel synthesis. As a general trend and as
anticipated, the average yield of this one-pot two-step process
synthesis was found to be slightly lower in the latter series, but
the described chemistry represents a viable method by which
inexpensive starting materials can be rapidly elaborated in
synthetically useful yields into more complex heterocycles of
pharmaceutical relevance.
ASSOCIATED CONTENT
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S
* Supporting Information
1
Experimental procedures, characterization and copies of H
NMR, 13C NMR, and LCMS data for all characterized
compounds highlighted in the manuscript. This material is
AUTHOR INFORMATION
Corresponding Author
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The author would like to thank Gilles Ouvry and Richard
Ducray for revising the manuscript and Christian Delvare and
Paul Davey for analytical support.
REFERENCES
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(1) Robinson, M. M; Finch, N. Imidazo(4,5-b)pyridines U.S. Patent
3719683, 1973.
(2) Luo, G.; Chen, L.; Conway, C. M.; Denton, R.; Keavy, D.;
Gulianello, M.; Huang, Y.; Kostich, W.; Lentz, K. A.; Mercer, S. E.;
et al. Discovery of BMS-846372, A Potent and Orally Active Human
CGRP Receptor Antagonist for the Treatment of Migraine. ACS Med.
Chem. Lett. 2012, 3, 337−341.
(3) Xu, F.; Zacuto, M.; Yoshikawa, N.; Desmond, R.; Hoerrner, S.;
Itoh, T.; Journet, M.; Humphrey, G. R.; Cowden, C.; Strotman, N.
Asymmetric Synthesis of Telcagepant, a CGRP Receptor Antagonist
for the Treatment of Migraine. J. Org. Chem. 2010, 75, 7829−7841.
(4) Lesher, G. Y.; Brundage, R. P.; Opalka, C. J.; Page, D. F.
Imidazo[4,5-b]pyridine derivatives useful as cardiotonics and prepara-
tion. French Patent 2478637, 1981.
(5) Kuczynski, L.; Mrozikiewiez, A.; Poreba, K. Synthesis and
Biological Properties of Pyrido[2, 3-d]pyridazine Derivatives. Pol. J.
Pharmacol. Pharm. 1982, 34, 229−234.
(6) Delluca, G. V.; Substituted cyclic ureas and derivatives thereof
useful as retroviral protease inhibitors. U.S. Patent 5763469, 1998.
(7) Kim, C. S.; Yang, K.; Jung, K. Y.; Park, S. Y.; Yoon, Y. H.; Lee, C.
S.; Hyu, C. S. Lee, K. H. Preparation of (imidazopyridiniummethyl)-
cephem compounds as antibacterials. Int. Patent WO 9429321, 1994.
(8) Choi, J. Y.; Plummer, M. S.; Starr, J.; Desbonnet, C. R.; Soutter,
H.; Chang, J.; Miller, J. R.; Dillman, K.; Miller, A. A.; Roush, W. R.
Structure Guided Development of Novel Thymidine Mimetics
Targeting Pseudomonas aeruginosa Thymidylate Kinase: From Hit to
Lead Generation. J. Med. Chem. 2012, 55, 852−870.
(9) Clark, R. L.; Pessolano, A. A.; Shen, T.-Y.; Jocobus, D. P.; Jones,
H.; Lotti, V. J.; Flataker, L. M. Synthesis and Analgesic Activity of 1,3-
Dihydro-3-(Substituted phenyl)imidazo[4,5-b]pyridin-2-ones and 3-
(Substituted phenyl)-1,2,3-triazolo[4,5-b]pyridines. J. Med. Chem.
1978, 21, 965−978.
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dx.doi.org/10.1021/co300078f | ACS Comb. Sci. 2012, 14, 491−495