Rapid synthesis of 3-amino-imidazopyridines by a microwave-assisted four-component coupling in one pot

Article abstract of DOI:10.1021/jo0622072

(Chemical Equation Presented) The rapid and efficient synthesis of various 2,6-disubstituted-3-amino-imidazopyridines using a microwave-assisted one-pot cyclization/Suzuki coupling approach is described. The utility of a 2-aminopyridine-5-boronic acid pin

Full text of DOI:10.1021/jo0622072

SCHEME 1. Retrosynthetic Analysis of Target
Compounds 1
Rapid Synthesis of 3-Amino-imidazopyridines by
a Microwave-Assisted Four-Component Coupling
in One Pot
Erin F. DiMauro* and Joseph M. Kennedy‡
Department of Medicinal Chemistry, Amgen Inc., One Kendall
Square, Building 1000, Cambridge, Massachusetts 02139
erin.dimauro@amgen.com
ReceiVed October 24, 2006
one-pot, microwave-assisted approach to this metal-catalyzed
multicomponent reaction (MCR) could prove useful in focused
library synthesis. Herein, we present a novel, divergent, and
expedient method to prepare amino-imidazopyridine libraries
from a common boronic ester building block. To the best of
our knowledge, this is the first example of an Ugi-type
cyclization of an aminopyridine in the presence of a boronate
functional group.
Previously, we reported a microwave-assisted, one-pot, two-
step cyclization/Suzuki coupling to access 2-substituted quinazo-
line imidazopyridines of general structure 3 (Scheme 2).6 The
tolerance of the boronic ester functionality in 2 to the acidic
conditions at elevated temperature (130 °C) during the cycliza-
tion is noteworthy. These results prompted further investigation
The rapid and efficient synthesis of various 2,6-disubstituted-
3-amino-imidazopyridines using a microwave-assisted one-
pot cyclization/Suzuki coupling approach is described. The
utility of a 2-aminopyridine-5-boronic acid pinacol ester as
a robust and versatile building block for the synthesis of
diverse compound libraries is emphasized. The boronate
functional group is remarkably tolerant to the Lewis acid
catalyzed cyclizations, and the subsequent Pd(0)-catalyzed
Suzuki coupling reactions proceed cleanly in the presence
of magnesium salts. This work highlights the vast potential
of microwave-assisted, metal-catalyzed, multicomponent
reactions.
(3) For recent reports of derivatization of functionalized boronic acids
and esters, see: (a) Holland, R.; Spencer, J.; Deadman, J. J. Synthesis 2002,
2379-2382. (b) Spencer, J.; Burd, A. P.; Goodwin, C. A.; Me´rette, S. A.
M.; Scully, M. F.; Adatia, T.; Deadman, J. J. Tetrahedron 2002, 58, 1551-
1556. (c) Zenk, R.; Partzsch, S. Chimica Oggi 2003, 21, 70-73. (d) Tyrrell,
E.; Brookes, P. Synthesis 2003, 4, 469-483. (e) McKiernan, G. J.; Hartley,
R. C. Org. Lett. 2003, 5, 4389-4392. (f) Bois-Choussy, M.; Cristau, P.;
Zhu, J. Angew. Chem., Int. Ed. 2003, 42, 4238-4241. (g) Kaiser, M.;
Siciliano, C.; Assfalg-Machleidt, I.; Groll, M.; Milbradt, A. G.; Moroder,
L. Org. Lett. 2003, 5, 3435-3437. (h) Schulz, M. J.; Coats, S. J.; Hlasta,
D. J. Org. Lett. 2004, 6, 3265-3268. (i) Lautens, M.; Mancuso, J. J. Org.
Chem. 2004, 69, 3478-3487. (j) Moore, J. E.; York, M.; Harrity, J. P. A.
Synlett 2005, 860-862. (k) Moore, J. E.; Davies, M. W.; Goodenough, K.
M.; Wybrow, R. A. J.; York, M.; Johnson, C. N.; Harrity, J. P. A.
Tetrahedron 2005, 61, 6706-6714. (l) Zhang, H.; Vogels, C. M.; Wheaton,
S. L.; Baerlocher, F. J.; Decken, A.; Westcott, S. A. Synthesis 2005, 2739-
2743. (m) Gravel, M.; Thompson, K. A.; Zak, M.; Berube, C.; Hall, D. G.
J. Org. Chem. 2002, 67, 3-15.
(4) (a) Georges, G. J.; Vercauteren, D. P.; Evrard, G. H.; Durant, F. V.;
George, P. G.; Wick, A. E. Eur. J. Med. Chem. 1993, 28, 323-335. (b)
Kaminski, J. J.; Wallmark, B.; Briving, C.; Andersson, B. M. J. Med. Chem.
1991, 34, 533-541. (c) Hamdouchi, C.; de Blas, J.; del Prado, M.; Gruber,
J.; Heinz, B. A.; Vance, L. J. Med. Chem. 1999, 42, 50-59. (d) Trapani,
G.; Franco, M.; Latrofa, A.; Ricciardi, L.; Carotti, A.; Serra, M.; Sanna,
E.; Biggio, G.; Liso, G. J. Med. Chem. 1999, 42, 3934-3941. (e) Lhassani,
M.; Chavignon, O.; Chezal, J.-M.; Teulade, J.-C.; Chapat, J.-P.; Snoeck,
R.; Andrei, G.; Balzarini, J.; De Clercq, E.; Gueiffier, A. Eur. J. Med. Chem.
1999, 34, 271-274. (f) Lo¨ber, S.; Hu¨bner, H.; Gmeiner, P. Bioorg. Med.
Chem. Lett. 1999, 9, 97-102. (g) Hibi, S.; Takahashi, Y.; Hoshino, Y.;
Kikuchi, K. S. M.; Yoshiuchi, T.; Shin, K.; Ono, M.; Shibata, H.; Ino, M.;
Hirakawa, T. WO 2002/062800, 2002. (h) Sundermann, B.; Sundermann,
C.; Hennies, H.-H.; Jostock, R. WO 2005/105798, 2005. (i) Kuehnert, S.;
Oberboersch, S.; Sundermann, C.; Haurand, M.; Jostock, R.; Schiene, K.;
Tzschentke, T.; Christoph, T.; Kaulartz, D. WO 2006/029980, 2006. (j)
Koch, K.; Hurley, T. B.; Yang, H.-W.; Lyssikatos, J.; Blake, J. F.; Marlow,
A. L.; Wallace, E. M. U. S. Pat. Appl. 2006030610, 2006. (k) Jinno, M.;
Shimokawa, H.; Yamagishi, T. WO 2006/064339, 2006.
The substituted 5,6-fused heterocyclic core is prevalent in
many synthetic and naturally occurring medicinal substances.1
Efforts in our laboratory are focused on extending the scope
and applications of microwave-assisted methods2 for the rapid
preparation of these ring systems from readily available,
functionalized boronic esters.3 The imidazo[1,2-a]pyridine
framework is common to several diverse classes of compounds
with medicinal value.4 Accordingly, we set out to develop a
convenient synthesis of 2,3,6-trisubstituted imidazo[1,2-a]py-
ridines (1) from commercially available 2-aminopyridine-5-
boronic acid pinacol ester (2)5 via an Ugi-type cyclization,
Suzuki coupling sequence (Scheme 1). We hypothesized that a
* To whom correspondence should be addressed. Tel: 617-444-5189. Fax:
617-621-3907.
‡
Boston College, Chestnut Hill, MA.
(1) (a) ComprehensiVe Heterocyclic Chemistry II: Fused FiVe- and Six-
Membered Rings with Ring Junction Heteroatom; Jones, G., Ed.; Perga-
mon: Oxford, UK, 1996; Vol. 8. (b) ComprehensiVe Heterocyclic Chemistry
II: Fused FiVe- and Six-Membered Rings without Ring Junction Heteroa-
tom; Ramsden, C. A., Ed.; Pergamon: Oxford, UK, 1996; Vol. 7.
(2) For a comprehensive review of microwave-accelerated metal catalysis,
see: Olofsson, K.; Larhed, M. In MicrowaVe Assisted Organic Synthesis;
Tierney, J. P., Lidstro¨m, P., Eds.; CRC Press: Boca Raton, FL, 2005; pp
23-43. For a comprehensive review of microwave-assisted heterocyclic
chemistry, see: Besson, T.; Braun, C. T. In MicrowaVe Assisted Organic
Synthesis; Tierney, J. P., Lidstro¨m, P., Eds.; CRC Press: Boca Raton, FL,
2005; pp 44-74.
(5) Available from Aldrich or Oakwood Products, Inc. Bulk quantities
available.
(6) DiMauro, E. F.; Vitullo, J. R. J. Org. Chem. 2006, 71, 3959-3962.
10.1021/jo0622072 CCC: $37.00 © 2007 American Chemical Society
Published on Web 12/24/2006
J. Org. Chem. 2007, 72, 1013-1016
1013

TABLE 1. Lewis/Brønsted Acid Catalyst Screen
SCHEME 2. Microwave-Assisted Preparation of
2-Substituted Quinazoline Imidazopyridines 3
cyclization
yield of 1a
entry
catalyst
(% conversion to 4a)d
(%)
into the potential utility of 2 as a robust and versatile building
block for the synthesis of diverse compound libraries.
1
2
3
4
5
6
7
8
none
61
67
84
85
80
88
83
80
80
0
32
35
33
62
46
65
54
65
60
-
montmorillonite K10c
p-TsOH
The preparation of fused amino-imidazo[1,2-a]heterocycles
via a Lewis or Brønsted acid catalyzed three-component Ugi-
type cyclization was first reported in 1998.7 Since then, few
groups have contributed to the further development and ap-
plication of this valuable methodology.8 Varma and Kumar
reported the montmorillonite K10-promoted three-component
coupling (3-CC) under solvent-free conditions in a conventional
microwave.8c Subsequently, Ireland et al. reported the microwave-
assisted 3-CC using 4% Sc(OTf)3 in MeOH at 160 °C for 10
min.8d More recently, Masquelin et al. used polymer-bound
Sc(OTf)3 to catalyze the microwave-mediated process, employ-
ing TMSCN as an isocyanide replacement.8e All three groups
reported moderate to good yields over a range of substrates.
We began our investigation with a microwave-assisted, one-
pot, two-step cyclization/Suzuki coupling to access amino-
imidazopyridine 1a. First, we conducted a brief Ugi-catalyst
screen (Table 1), using the catalysts reported by Varma (entry
2), Ireland (entry 4), and Masquelin (entry 5), as well as other
conventional Brønsted (HA) and Lewis acids (LA). Although
the cyclization generally proceeded to near completion with all
of the catalysts tested, the subsequent Suzuki reaction was
apparently perturbed by the presence of certain HA or LA
additives in the pot. We were delighted to find that the isolated
yield of 1a was highest with inexpensive LA catalysts AlCl3
and MgCl2 (entries 6 and 8). With both catalysts, the cyclization9
was very clean and the two minor byproducts observed in the
Suzuki reaction resulted from protodeboronation and coupling
of remaining 2 to 3-bromoanisole. Interestingly, an attempt to
promote the Ugi reaction with Suzuki catalyst Pd(dppf)Cl2 was
not successful. In fact, the cyclization was almost completely
suppressed. At this time, we are unable to explain the lack of
cyclization in the presence of catalytic (10%) palladium.
Sc(OTf)3
PS-Sc(OTf)3
AlCl3
Si-AlCl3
MgCl2
9a
10b
MgCl2
Pd(dppf)Cl2
a CH3CN was used instead of MeOH. b 10% catalyst was used. c 30
wt %. d % conversion determined by LCMS (ratio 4a/2).
TABLE 2. Suzuki Screen (One-Pot Conversion of 2 to 1a)a
T
t
yield of 1a
entry
catalyst
base
none
(°C)d
(min)d
(%)
1
2
3
4
5
6b
7
8
Pd(dppf)Cl2
Pd(dppf)Cl2
Pd(dppf)Cl2
Pd(dppf)Cl2
Pd(dppf)Cl2
Pd(dppf)Cl2
Pd(PPh3)2Cl2
Pd(PPh3)4
90
90
90
90
120
90
30
30
30
60
30
30
30
30
0
30
65
60
59
54
40
0
CsF
c
c
c
c
c
c
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
90
90
a Step 1: 1.0 equiv of 2, 1.0 equiv of BnNC, 1.0 equiv of PhCHO, 0.04
equiv of MgCl2, 160 °C, 10 min, µW. Step 2: 1.0 equiv of 3-bromoanisole,
0.10 equiv of catalyst, 2.5 equiv of base, µW. b 1.3 equiv of 3-bromoanisole.
c 2.0 M aqueous solution. d T and t for step 2.
To examine the Suzuki reaction in more detail, we conducted
a brief screen of palladium catalysts and reaction conditions
(Table 2). The aqueous carbonate base proved superior to
fluoride for activation of the boronate (entry 3 vs entry 2).
Increasing the reaction time (entry 4) or temperature (entry 5)
did not improve the yield of 1a. Because the minor product
resulting from Suzuki coupling of uncyclized 2 and 3-bromoani-
sole was frequently observed, we attempted the reaction using
excess 3-bromoanisole (entry 6); no improvement was observed
under these conditions. The use of Pd(PPh3)2Cl2 (entry 7) or
Pd(PPh3)4 (entry 8) as the catalyst led to a significant decrease
in turnover and yield.
Having identified suitable conditions for cyclization and
Suzuki coupling, we conducted an extensive substrate scope
study (Table 3). The reaction scope is quite broad with respect
to the aldehyde (R1) and bromide (R3) components. Electron-
rich, electron-poor, aromatic, aliphatic, and sterically encum-
bered substrates were all well tolerated. Furthermore, to the best
of our knowledge, the isolation of 1i, 1k, and 1o represents the
first successful inclusion of paraformaldehyde as the aldehyde
component in the Ugi-type cyclization of an amino-
pyridine, providing convenient access to 3,6-disubstituted imi-
dazo[1,2-a]pyridines.
(7) (a) Blackburn, C.; Guan, B.; Fleming, P.; Shiosaki, K.; Tsai, S.
Tetrahedron Lett. 1998, 39, 3635-3638. (b) Groebke, K.; Weber, L.;
Mehlin, F. Synth. Lett. 1998, 661-662. (c) Bienayme´, H.; Bouzid, K. Angew.
Chem., Int. Ed. 1998, 37, 2234-2237.
(8) (a) For, a review of isocyanide-based MCRs, see: Doemling, A.
Chem. ReV. 2006, 106, 17-89. (b) For a review of Ugi MCRs, see:
Tempest, P. A. Curr. Opin. Drug DiscoVery DeV. 2005, 8, 776-788. For
microwave-promoted adaptations, see: (c) Varma, R. S.; Kumar, D.
Tetrahedron Lett. 1999, 40, 7665-7669. (d) Ireland, S. M.; Tye, H.;
Whittaker, M. Tetrahedron Lett. 2003, 44, 4369-4371. (e) Masquelin, T.;
Bui, H.; Brickley, B.; Stephenson, G.; Schwerkoske, J.; Hulme, C.
Tetrahedron Lett. 2006, 47, 2989-2991. (f) Lu, Y.; Zhang, W. QSAR Comb.
Sci. 2004, 23, 827-835. For solid-supported adaptations, see: (g) Blackburn,
C.; Guan, B. Tetrahedron Lett. 2000, 41, 1495-1500. (h) Chen, J. J.;
Golebiowski, A.; McClenaghan, J.; Klopfenstein, S. R.; West, L. Tetrahe-
dron Lett. 2001, 42, 2269-2271. (i) Lyon, M. A.; Kercher, T. S. Org. Lett.
2004, 6, 4989-4992.
(9) Extending the reaction time for the cyclization to 20 min did not
improve the conversion to 4a.
1014 J. Org. Chem., Vol. 72, No. 3, 2007

TABLE 3. Substrate Scope
a Average of three reactions. b Average of two reactions. c Paraformaldehyde; cyclization t ) 20 min. d % conversion determined by LCMS (ratio 4/2).
The one-pot, two-step process is quite general for alkyl
isocyanides, and moderate yields are consistently obtained
(1a-m). Importantly, the reaction proceeds well with 1,1,3,3-
tetramethylbutylisocyanide, which has previously been demon-
strated to be a surrogate for the cyanide anion because the
tetramethylbutylamine products, such as 1k-m, can be readily
J. Org. Chem, Vol. 72, No. 3, 2007 1015

SCHEME 3. Example of Facile Deprotection of
Tetramethylbutylamine Products: Preparation of 1p
versatile building block for the synthesis of a diverse amino-
imidazo[1,2-a]pyridine library (1). This highly practical and
operationally simple method underscores the enormous potential
of microwave-assisted, metal-catalyzed, multicomponent
reactions.
Experimental Section
General Method for the Preparation of 1a-m and 1o. To a
2-5 mL microwave reaction vessel were added 2-aminopyridine-
5-boronic acid pinacol ester (2) (200 mg, 0.91 mmol), isocyanide
(0.91 mmol), aldehyde (0.91 mmol), MgCl2 (3.4 mg, 0.036 mmol),
and anhydrous MeOH (3.5 mL). The vessel was sealed and purged
with N2. The mixture was heated in a laboratory microwave at 160
°C for 10 min (20 min for 1l and 1o) then allowed to cool to room
temperature. The vessel was opened, and bromide (0.91 mmol),
2.0 M K2CO3 (1.14 mL, 2.28 mmol), and Pd(dppf)Cl2 (73 mg, 0.09
mmol) were added to it. The vessel was resealed and purged with
N2. The mixture was heated in the microwave for 30 min at 90 °C
then allowed to cool to room temperature. The contents of the vessel
were filtered through celite and washed with CH2Cl2. Organic
solvents were evaporated, and the crude solid was purified on
preparative HPLC (eluent: 0.1% TFA in aqueous solution and 0.1%
TFA in acetonitrile). The product fractions were combined and
washed with saturated aqueous NaHCO3 and extracted with CH2-
Cl2. Organic solvents were evaporated to yield the title compound.
N-Benzyl-6-(3-methoxyphenyl)-2-phenyl-imidazo[1,2-a]pyri-
din-3-amine (1a): 0.214 g (58.0%), brown solid; HPLC 100.0%;
converted to the primary amines upon treatment with TFA.8g
For example, 1l was converted to the corresponding primary
amine (1p, R2 ) H) in 89% yield, using 1:1 CH2Cl2/TFA
(Scheme 3).
Although the Ugi cyclization with 2,6-dimethylphenyliso-
cyanide and nicotinaldehyde proceeded relatively cleanly, the
boronate intermediate failed to couple with a variety of aryl
bromides under the usual Suzuki conditions (entry 14).10 We
reasoned that the bulky 2,6-dimethylphenyl group at R2 was
conformationally biased by proximity to the pyridine at R1 and
therefore posed a steric hindrance to the Suzuki reaction. With
paraformaldehyde as the aldehyde component, 2,6-dimethylphe-
nylisocyanide underwent clean Ugi-type cyclization and sub-
sequent Suzuki coupling to afford 1o in 60% yield (entry 15).
Attempts to perform the 4-CC in one step were not successful.
Reaction of 2, benzaldehyde, benzylisocyanide, and 3-bro-
moanisole in the presence of aq K2CO3, 10% Pd(dppf)Cl2, and
4% MgCl2 (160 °C, 30 min, µW) resulted in the formation of
multiple products. The alternative one-pot, sequential reaction
sequence (i.e., Suzuki then cyclization) was not feasible.
Although the Suzuki reaction was very clean and proceeded to
completion, no cyclized product was observed after subjecting
the crude 5-(3-methoxyphenyl)pyridin-2-amine to the typical
Ugi conditions (benzaldehyde, benzylisocyanide, 4% MgCl2,
30 min, µW). For these reactions, we speculate that the presence
of aqueous base in the reaction pot severely retards the
cyclization, presumably by inactivating the Lewis acid catalyst.
In conclusion, we have demonstrated the utility of the
2-aminopyridine-5-boronic acid pinacol ester (2) as a robust and
1
HRMS calcd for [C27H24N3O]+ 406.19139, found 406.19255; H
NMR (400 MHz, DMSO-d6) δ 8.38 (s, 1H), 8.23 (d, J ) 7.2 Hz,
2H), 7.53-7.39 (m, 5H), 7.33-7.15 (m, 8H), 6.97 (dd, J ) 8.1,
2.4 Hz, 1H), 5.50 (t, J ) 6.4 Hz, 1H), 4.15 (d, J ) 6.3 Hz, 2H),
3.85 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ 159.8, 140.0, 139.7,
138.4, 134.5, 134.3, 130.1, 128.4, 128.2, 128.1, 127.3, 127.1, 126.9,
126.4, 124.0, 123.7, 120.3, 118.7, 116.7, 112.9, 112.0, 55.2, 51.5.
Acknowledgment. J.M.K. thanks Amgen Inc. for a summer
internship.
Supporting Information Available: Experimental details for
the preparation of 1p and characterization of all new compounds
including analytical data for 1a-m and 1o,p. This material is
available free of charge via the Internet at http://pubs.acs.org.
(10) Similarly, no Suzuki coupling is observed using 4-bromopyridine
or 5-bromopyrimidin-2-amine instead of 1-bromo-3-methoxybenzene. No
coupling is observed when excess base (5 equiv of K2CO3) is used.
JO0622072
1016 J. Org. Chem., Vol. 72, No. 3, 2007