Synthesis of imidazo[4,5-b]pyridines and imidazo[4,5-b]pyrazines by palladium catalyzed amidation of 2-chloro-3-amino-heterocycles

Article abstract of DOI:10.1021/ol300359s

A facile synthesis of imidazo[4,5-b]pyridines and-pyrazines is described using a Pd-catalyzed amide coupling reaction. This reaction provides quick access to products with substitution at N1 and C2. A model system relevant to the natural product pentosidi

Full text of DOI:10.1021/ol300359s

ORGANIC
LETTERS
2012
Vol. 14, No. 7
1764–1767
Synthesis of Imidazo[4,5-b]pyridines and
Imidazo[4,5-b]pyrazines by Palladium
Catalyzed Amidation of 2-Chloro-3-amino-
heterocycles
Adam J. Rosenberg, Jinbo Zhao, and Daniel A. Clark*
Department of Chemistry, 1-014 Center for Science and Technology,
Syracuse University, Syracuse, New York 13244, United States
daclar01@syr.edu
Received February 14, 2012
ABSTRACT
A facile synthesis of imidazo[4,5-b]pyridines and -pyrazines is described using a Pd-catalyzed amide coupling reaction. This reaction provides
quick access to products with substitution at N1 and C2. A model system relevant to the natural product pentosidine has been demonstrated, as
well as the total synthesis of the mutagen 1-Me-5-PhIP.
Efficient catalytic methods for the synthesis of imidazo-
[4,5-b]pyridines, especially those bearing N1 substitution, are
in demand. Imidazo[4,5-b]pyridine derived structures are of
growing interest due to their ability to function as biological
mimics of the well-explored and highly developed benzimi-
dazole core structure.1À3 Imidazo[4,5-b]pyridine derived mole-
cules possess diverse pharmacological properties,4 including
anticancer,5,6 antiviral,7,8 and other important biological
activities.9À16
Despite the importance of these structures, imidazo-
[4,5-b]pyridines are difficult to prepare in a regioselective
manner, especially with substitution at the N1-position.
(10) Bavetsias, V.; Large, J. M.; Sun, C.; Bouloc, N.; Kosmopoulou,
M.; Matteucci, M.; Wilsher, N. E.; Martins, V.; Reynisson, J. h.; Atrash,
B.; Faisal, A.; Urban, F.; Valenti, M.; de Haven Brandon, A.; Box, G.;
Raynaud, F. I.; Workman, P.; Eccles, S. A.; Bayliss, R.; Blagg, J.;
Linardopoulos, S.; McDonald, E. J. Med. Chem. 2010, 53, 5213–5228.
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r
10.1021/ol300359s
Published on Web 03/13/2012
2012 American Chemical Society

(Figure 1). Alkylation of the unsubstituted imidazo[4,5-b]-
pyridine is remarkably unselective. For example, with
sodium hydride and benzylbromide a 1:3.6:1.6 (N1:N3:
N4) ratio of products has previously been observed.17 The
same problem exists for benzimidazole, as regioisomers are
generally observed when the aryl moiety is substituted.18
Thus, we sought to develop a practical and selective method
for the formation of N1 substituted imidazo[4,5-b]pyridines.
A route that could grant access to analogues with substitu-
tion of hydrogen, carbon, halogens, and heteroatoms at C2
was highly desirable. We believe a protocol that incorpo-
rates all these criteria would represent a significant advance
in this area of heterocyclic chemistry.
Figure 1. Imidazo[4,5-b]pyridine containing molecules of interest.
Many attempts have been made to address these issues. In
1994 Senanayake et al. reported a multistep sequence utilizing
1,3-diketones, malonamamidine salts, and carboxylic acids to
give 2-alkyl substituted imidazo[4,5-b]pyridines; however, no
substitution at N1 or N3 was reported.19 Other methods
usually require expensive 2,3-diaminopyridines as a starting
material and/or proceed in a moderate yield.18 As such, we
choose to explore a metal-catalyzed cross-coupling route. This
would allow greater product diversity and the use of the less
expensive 2-chloro-3-aminopyridine.
Transition-metal catalyzed cross-coupling reactions
have become a reliable, efficient method for CÀC and
CÀheteroatom bond formations.20À23 Pd-catalyzed CÀN
couplings have become an increasingly important tool in
heterocycle synthesis.24À26 Recently Buchwald27 and Ma28
independently developed complementary syntheses of
imidazo[4,5-b]pyridinesusing2-halo-3-acylaminopyridines
and amines to give N3-substituted products, with alkyl
substitution at C2. However, these approaches did not
allow substitution at N1 or heteroatom substitution at C2.
Also, alkyl amines performed poorly in this reaction due to
facile β-hydride elimination of the Pd(II) intermediates.27
Buchwald and Zheng recently demonstrated that benzimi-
dazole formation tolerated alkylamines when copper was
utilized as a catalyst.29 Ma’s approach similarly utilized
proline-bound copper which produced N3-substituted
imidazo[4,5-b]pyridines.28,30
Our interest in imidazo[4,5-b]pyridines originates from
our work toward the total synthesis of pentosidine
(Figure 1). We desired an economical method to produce
imidazo[4,5-b]pyridines with an electron-donating group
at the N1-position31 and an amine at the 2-position. Herein
we report a modular method for the preparation of the
imidazo[4,5-b]pyridines present in the core of pentosidine
and in the Aurora kinase inhibitor lead CCT12920210,11,32
(Figure 1) through Pd-catalyzed coupling of amides and
2-chloro-3-amino pyridines (Scheme 1).
Our approach is conceptually distinct from those of
Buchwald and Ma as we couple a protected 2-chloro-3-
aminopyridine with a primary amide, followed by subse-
quent in situ cyclization and dehydration to provide the
imidazo[4,5-b]pyridine core in a single reaction vessel26,33
(Scheme 1). Protected 3-amino-2-chloropyridines are easily
generatedonamultigramscaleby reductive amination of the
readily available and inexpensive chloro-aminopyridines.34
We began our studies with known chloropyridine 2a.
This compound is highly crystalline, and the product pos-
sessed the electron-donating group at N1 which we desired
for our synthesis of pentosidine.
(17) Khanna, I. K.; Weier, R. M.; Lentz, K. T.; Swenton, L.; Lankin,
D. C. J. Org. Chem. 1995, 60, 960–965.
(18) M.Ross, G. Imidazole and Benzimidazole Synthesis; Academic
Press: San Diego, 1997.
(19) Senanayake, C. H.; Fredenburgh, L. E.; Reamer, R. A.; Liu, J.;
Larsen, R. D.; Verhoeven, T. R.; Reider, P. J. Tetrahedron Lett. 1994, 35,
5775–5778.
(20) Jiang, L.; Buchwald, S. L. Metal-Catalyzed Cross-Coupling
Reactions; Wiley-VCH Verlag GmbH: 2008; pp 699À760.
(21) Tsuji, J. Palladium Regents and Catalysts: Innovation in Organic
Synthesis; John Wiley & Sons: New York, 1995.
(22) (a) Negishi, E. Handbook of Organopalladium Chemistry for
Organic Synthesis; John Wiley & Sons: New York, 2002; Vols. 1 and 2.
(b) Tsuji, J. Palladium Reagents and Catalysts: New Perspectives for the
21st Century; John Wiley & Sons: New York, 2004.
(23) For recent references associated with the coupling of 2-chloro-
pyridine and amines, see: (a) Tardiff, B. J.; McDonald, R.; Ferguson,
M. J.; Stradiotto, M. J. Org. Chem. 2012, 77, 1056–1071. (b) Lundgren,
R. J.; Sappong-Kumankumah, A.; Stradiotto, M. Chem.;Eur. J. 2010,
16, 1983–1991. (c) Shankaraiah, N.; Santos, L. S. Tetrahedron Lett.
2008, 50, 520–523. For coupling with amides: (d) Shen, Q.; Shekhar, S.;
Stambuli, J. P.; Hartwig, J. F. Angew. Chem., Int. Ed. 2005, 44, 1371–
1375 and references cited therein.
Initial efforts to couple pyridine 2a and formamide
with standard phosphine ligands (Table 1, entries 1À5;
Figure 2) did not show the desired reactivity, presumably
due to κ2 coordination of the formamide to the Pd center.35,36
(29) Zheng, N.; Buchwald, S. L. Org. Lett. 2007, 9, 4749–4751.
(30) While this manuscript was in preperation, You and co-workers
published a palladium catalyzed coupling to produce N1/C2 aryl sub-
stituted imidazo[4,5-b]pyridines and pyrazines. Zhao, D.; Hu, J.; Wu,
N.; Huang, X.; Qin, X.; Lan, J.; You, J. Org. Lett. 2011, 13, 6516–6519.
(31) Sugiyama, H.; Yokokawa, F.; Shioiri, T.; Katagiri, N.; Oda, O.;
Ogawa, H. Tetrahedron Lett. 1999, 40, 2569–2572.
(32) Lan, P.; Chen, W.-N.; Chen, W.-M. Eur. J. Med. Chem. 2011, 46,
77–94.
(33) Surry, D. S.; Buchwald, S. L. Chem. Sci. 2011, 2, 27–50.
(34) McLaughlin, M.; Palucki, M.; Davies, I. W. Org. Lett. 2006, 8,
3307–3310.
(24) Wagaw, S.; Yang, B. H.; Buchwald, S. L. J. Am. Chem. Soc.
1998, 120, 6621–6622.
(25) Maes, B.; Van der Eycken, E.; Kappe, C. In Transition-Metal-
Based CarbonÀCarbon and CarbonÀHeteroatom Bond Formation for the
Synthesis and Decoration of Heterocycles; Springer Berlin/Heidelberg:
2006; Vol. 1, pp 155À211.
(26) Surry, D. S.; Buchwald, S. L. Angew. Chem., Int. Ed. 2008, 47,
6338–6361.
(27) Zheng, N.; Anderson, K. W.; Huang, X.; Nguyen, H. N.;
Buchwald, S. L. Angew. Chem., Int. Ed. 2007, 46, 7509–7512.
(28) Zou, B.; Yuan, Q.; Ma, D. Angew. Chem., Int. Ed. 2007, 46,
2598–2601.
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Org. Lett., Vol. 14, No. 7, 2012
1765

Table 1. Reaction Optimizationa
Scheme 1. Transition-Metal Catalyzed Cross-Coupling Ap-
proaches for the Synthesis of Imidazo[4,5-b]pyridines
Next we explored ligands which have recently been shown to
be effective in coupling aryl halides with amides. Both Me4-
tBu-XPhos35 (entry 8) and t-BuBrettPhos37 (entry 9) gave the
desired product 3a in excellent yield. The Bippyphos ligand38
gave only a moderate yield of 3a (entry 7). Control experi-
ments indicated there was no reaction in the absence of Pd; the
absence of ligand also afforded no product. Additionally, no
SNAr products were obtained in the absence of both Pd and
ligand. When taken together, these experiments lend evidence
to a metal catalyzed cross-coupling mechanism operating
under the reaction conditions (entries 10À12). Potassium
phosphate base and tert-butanol solvent have been previously
used for coupling amides and aryl halides;35 they performed
well here, granting the desired products in e4 h in all cases
under optimized conditions.
With optimized reaction conditions in hand, we ex-
plored the reaction scope. As shown in Table 2 the reaction
produces the desired imidazo[4,5-b]pyridines in good to
excellent yields with substituted benzyl derivatives (entries
1À4). Importantly, an aryl chloride (i.e., 2-chlorobenzyl)
was tolerated under the reaction conditions (entry 5).
Pyridine substitution was well tolerated at N1 despite
pyridine’s known ability to compete with ligands on Pd
(entry 6).39,40 Alkyl substitution was also well tolerated,
and no β-hydride elimination was encountered in this
reaction (entries 7À12). Excellent yields were obtained
for both branched and unbranched alkyl groups. Compat-
ibility of chiral substitution at the 1-position was also
demonstrated (entries 13 and 14), and the products were
isolated without racemization of either isomer 3m or 3n.41
a Reaction conditions: 2a (0.4 mmol), Pd (0.004 mmol, 1 mol %),
ligand (0.02 mmol, 5 mol %), 2 mL of t-BuOH (0.2 M), 110 °C, 4 h.
b Yields are of isolated products.
Chiral substrates 2m and 2n were prepared through the
known BuchwaldÀHartwig coupling of 3-iodo-2-chloro-
pyridine with the desired amine.42 Both phenyl and
4-methoxyphenyl aryl substitutions were well tolerated
(entries 15 and 16). Aryl substitution at N1 was installed
by ChanÀLam coupling with the corresponding arylboro-
nic acids.43,44
Although alkyl and aryl substitution at the 2-position of
the imidazo[4,5-b]pyridine was not our primary objective,
the reaction performs well when the formamide was ex-
changed for either benzamide or acetamide to give the
phenyl (8) and methyl (9) substituted products respectively
(Scheme 2). Other substituted amides such as cyclohexane-
carboxamide coupled in 89% yield but failed to undergo the
dehydrative cyclization, while cinnamamide gave a 3:1
mixture of uncyclized to cyclized products in 92% yield.45
Substitution at both the 4- and 6-positions of the pyridine
was well tolerated and afforded 10 and 11 in excellent yields.
Pyrazines performed particularly well under the stan-
dard reaction conditions; the desired imidazo[4,5-b]pyrazines
12 and 13 were isolated in excellent yield with the reaction
taking place up to 8-fold faster (Scheme 2). We ascribe this
(36) We briefly explored copper catalyzed conditions, unfortunately
without success.
(37) Fors, B. P.; Watson, D. A.; Biscoe, M. R.; Buchwald, S. L. J. Am.
Chem. Soc. 2008, 130, 13552–13554.
(38) Withbroe, G. J.; Singer, R. A.; Sieser, J. E. Org. Process Res.
Dev. 2008, 12, 480–489.
(39) Paul, F.; Patt, J.; Hartwig, J. F. Organometallics 1995, 14, 3030–
3039.
(40) Wagaw, S.; Buchwald, S. L. J. Org. Chem. 1996, 61, 7240–7241.
(41) Chiral purity determined by chiral HPLC.
(42) Kuethe, J. T.; Wong, A.; Davies, I. W. J. Org. Chem. 2004, 69,
7752–7754.
(43) Chan, D. M. T.; Monaco, K. L.; Wang, R.-P.; Winters, M. P.
Tetrahedron Lett. 1998, 39, 2933–2936.
(44) Evans, D. A.; Katz, J. L.; West, T. R. Tetrahedron Lett. 1998, 39,
2937–2940.
Figure 2. Phosphine ligands.
(45) Isolated yield, ratio determined via 1H NMR.
1766
Org. Lett., Vol. 14, No. 7, 2012

Table 2. Reaction Scopea
Scheme 3. Product Functionalization
tively deprotonated with LDA at low temperature, and sub-
sequently quenched with electrophiles46 (Scheme 3, eq 1).
We choose iodine as an electrophile to demonstrate the
potential of this reaction which produced 14 in 84% yield.
Further functionalization of 14 by SNAr with amines as the
nucleophiles illustrates the utility of our methodology for
the synthesis of pentosidine (eq 2).47,48 Alternatively, direct
functionalization via Chichibabin amination49,50 was also
performed to provide known mutagen 1-Me-5-PhIP 1751
from 11 in 95% yield. This represents a short and high
yielding synthesis of this naturally occurring N1 substituted
imidazo[4,5-b]pyridine.
a Reaction conditions: 2 (0.4 mmol), Pd (0.004 mmol, 1 mol %),
ligand (0.02 mmol, 5 mol %), 2 mL of t-BuOH (0.2 M), 110 °C, 4 h.
b Yields are of isolated products. c Cyp = Cyclopentyl.
Scheme 2. Reaction Scopea,b
In summary, we have developed a regioselective Pd-
catalyzed method for the synthesis of imidazo[4,5-b]pyrid-
ines and -[4,5-b]pyrazines. The current protocol is comple-
tely selective and grants high yielding access to regio-
isomers that are difficult to obtain using previous methods.
Our method is complementary to the methods developed by
Buchwald27 and Ma,28 as N1 substituted isomers can now
be obtained through metal catalyzed coupling. In addition,
we have shown the potential for further functionalization by
installation of primary, secondary, and tertiary amines at
the 2-position. We are currently exploring the extension of
this methodology to other chloro-amino heterocycles for
the synthesis of nitrogen-rich bicyclic systems.
a Reaction conditions: Pyr (0.4 mmol), Pd (0.004 mmol, 1 mol %),
ligand (0.02 mmol, 5 mol %), 2 mL of t-BuOH (0.2 M), 110 °C, 4 h.
bYields are of isolated products. cL2 was used. dL1 was used. e2 h. f0.5 h.
rate enhancement to faster oxidative addition with the
electron-deficient pyrazine moiety.
One advantage of our method is that C2 can be easily
functionalized. The 2-position is acidic and can be selec-
Acknowledgment. We thank Syracuse University for
the generous financial support of this research. We thank
the Chisholm and Totah groups (Syracuse University) for
copious sharing of chemicals, use of instrumentation, and
helpful discussions. We thank Ms. Tara Brenner (Clark
group) for the synthesis of 2a and 2d.
(46) Gschwend, H. W.; Rodriguez, H. R. Organic Reactions; John
Wiley & Sons, Inc.: 2004, pp 1À360.
(47) Jiang, H.; Congleton, J.; Liu, Q.; Merchant, P.; Malavasi, F.;
Lee, H. C.; Hao, Q.; Yen, A.; Lin, H. J. Am. Chem. Soc. 2009, 131, 1658–
1659.
Supporting Information Available. Experimental pro-
cedures and characterization data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(48) Jin, C.; Burgess, J. P.; Rehder, K. S.; Brine, G. A. Synthesis 2007,
219–224.
(49) Choshi, T.; Tonari, A.; Yoshioka, H.; Harada, K.; Sugino, E.;
Hibino, S. J. Org. Chem. 1993, 58, 7952–7954.
(50) Makosza, M.; Wojciechowski, K. Chem. Rev. 2004, 104, 2631–
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The authors declare no competing financial interest.
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