An expeditious approach to access 2-arylimidazo[1,2-a]pyridin-3-ol from 2-amino pyridine through a novel Petasis based cascade reaction

Article abstract of DOI:10.1016/j.tetlet.2013.12.018

An expeditious cascade protocol for the synthesis of functionalized imidazo[1,2-a]pyridin-3-ols was developed based on the Petasis reaction. With the availability of commercial reagents and high efficiency in expanding molecule diversity, this methodology is superior to the existing procedures for the synthesis of imidazo-pyridin-3-ol analogues.

Full text of DOI:10.1016/j.tetlet.2013.12.018

Tetrahedron Letters 55 (2014) 1281–1284
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
An expeditious approach to access 2-arylimidazo[1,2-a]pyridin-3-ol
from 2-amino pyridine through a novel Petasis based cascade
reaction
,à
⇑
Yuanxiang Wang , Biswajit Saha , Fang Li, Brendan Frett, Hong-yu Li
College of Pharmacy, Department of Pharmacology and Toxicology, The University of Arizona, Tucson, USA
BIO-5 Oro Valley, The University of Arizona, Ora Valley, AZ 85737, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
An expeditious cascade protocol for the synthesis of functionalized imidazo[1,2-a]pyridin-3-ols was
developed based on the Petasis reaction. With the availability of commercial reagents and high efficiency
in expanding molecule diversity, this methodology is superior to the existing procedures for the synthesis
of imidazo-pyridin-3-ol analogues.
Received 19 October 2013
Revised 2 December 2013
Accepted 6 December 2013
Available online 12 December 2013
Ó 2014 Published by Elsevier Ltd.
Keywords:
Cascade reaction
Petasis reaction
MCR
2-Arylimidazo[1,2-a]pyridine-3-ol
Multicomponent reactions (MCRs) are one of the most efficient
methods to rapidly increase molecular complexity. MCRs feature
abundant potential reagent combinations, inputs, and post-MCR
modifications, which results in exceptionally high diversification
power.1 MCRs are known for atom economy, convergent character,
operational simplicity, and structural diversity and complexity of
the resulting molecules making MCR based chemistry extremely
useful for the discovery and optimization of a lead molecule.2
Among the various MCRs, the Petasis reaction (Petasis borono–
Mannich reaction) has received much attention due to its power
to produce various substituted amino acids and heterocyclic com-
pounds.3 The Petasis reaction results from the reaction between an
aldehyde, an amine, and a boronic acid to form product 4 and boric
acid 5 (Scheme 1).
In the past two decades, several modifications of the Petasis
reaction have been reported. Naskar et al. took advantage of the
Petasis reaction to prepare carboxylic acid using N-substituted
indoles as an amine equivalent.4 In another example of Petasis
modification, Naskar et al. replaced the indoles with tertiary
aromatic amines to afford substituted phenylacetic acid.5 With
also be synthesized enantioselectively through the Petasis reac-
tion.7 However, the Petasis based cascade reaction has rarely been
reported.8
In view of our continued interest in the synthesis of drug-like
molecules through MCRs9 for our high-throughput screening
(HTS) program, we initially intended to perform a three-compo-
nent Petasis reaction between 2-amino-5-methyl-pyridine (6), 4-
methoxy phenyl boronic acid (7), and glyoxylic acid (8) to get ami-
no acid 9 under microwave irradiation,10 but we obtained a three-
component Petasis reaction followed by a cascade cyclization, gen-
erating 2-(4-methoxyphenyl)-6-methylimidazo[1,2-a]pyridin-3-ol
(Compound 10, Scheme 2).
Since imidazo[1,2-a]pyridin-3-ol with 2-aryl substituents dis-
play antifungal and anthelmintic activity,11 two different proce-
dures have been developed to synthesize these compounds.12
One strategy is the condensation of 2-aminopyridine with
substituted glyoxal,12a,b and the other is the reaction between
pyridin-2-amine 1-oxides and phenacyl bromides.12c,d But, the
two reported synthetic methods suffer from low efficiency in
expanding molecular diversity because few substituted glyoxals
and pyridin-2-amine 1-oxides are commercially available.
a
-hydroxy aldehyde used as a substrate, Pyne et al. utilized the
Petasis reaction to furnish amino alcohols.6 b-Amino alcohols can
R2
R4
R3
R1
R2
N
R4
B
O
N
+
B(OH)3
+
⇑
+
Corresponding author. Tel.: +1 520 626 0794.
E-mail address: hongyuli@pharmacy.arizona.com (H. Li).
Y.W. and B.S. contributed equally.
Present address: Department of Chemistry, Apeejay Stya University, Sohna,
H
R3
R1
H
HO
OH
5
3
2
1
4
à
Gurgaon, Haryana 122003, India.
Scheme 1. The Petasis borono–Mannich reaction.
0040-4039/$ - see front matter Ó 2014 Published by Elsevier Ltd.
http://dx.doi.org/10.1016/j.tetlet.2013.12.018

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Y. Wang et al. / Tetrahedron Letters 55 (2014) 1281–1284
O
N
O
MW
OH
O
+
+ O
B(OH)2
N
O
N
NH2
OH
OH
N
N
H
8
6
10
7
O
9
Scheme 2. The synthesis of Compound 10.
Table 1
Optimization of reaction conditionsa
N
O
OH
O
+
MW
+
O
N
O
8
B(OH)2
N
NH2
OH
10
7
6
Entry
Solvent
Reaction condition
Yieldb (%)
1
2
3
4
5
6
7
8
9
MeCN
MeCN
DMF–MeCN (1:1)
DMF
DMF
DMF
DMF
EtOH
CF3CH2OH
(CF3)2CHOH
20 min 100 °C
30 min 100 °C
30 min 100 °C
30 min 100 °C
30 min 120 °C
30 min 140 °C
30 min 160 °C
30 min 120 °C
30 min 120 °C
30 min 120 °C
20
35
38
40
48
65
80
30
50
75
10
a
Unless noted, the reaction was conducted with 1 mmol 6, 1 mmol 7, and 1 mmol 8 in 3 mL solvent.
Isolated yield.
b
Table 2
Substrate scope of aminopyridinel
R
N
O
OH
MW
O
R
+
+
O
N
O
B(OH)2
N
NH2
OH
Entry
1
Aminopyridine
Product
Yielda (%)
80
N
O
N
N
NH2
OH
N
O
N
NH2
2
85
N
N
N
OH
N
O
O
3
4
66
48
N
NH2
OH
N
N
N
NH2
OH
Br
Br
N
5
6
O
40
NH2
N
OH
N
Br
N
O
O
48
53
Br
Cl
N
NH2
OH
Cl
N
N
N
7
OH
NH2
a
Isolated yields obtained using 1 mmol aminopyridine, 1 mmol 7, 1 mmol 8 in DMF at 160 °C for 30 min under microwave irradiation.

Y. Wang et al. / Tetrahedron Letters 55 (2014) 1281–1284
1283
Therefore utilizing MCR-based chemistry, we developed a more
practical method allowing for the expeditious access to imi-
dazo[1,2-a]pyridine-3-ol from commercially available reagents.
This facile procedure is in high demand permitting rapid structural
diversification of imidazo[1,2-a]pyridin-3-ol. In this Letter we de-
scribe the synthesis of imidazo-pyridin-3-ol analogues through a
Petasis based cascade reaction using 2-aminopyridine, glyoxylic
acid, and boronic acid.
To establish efficient and appropriate reaction conditions, we
first selected 6, 7, and 8 as substrates and examined time, solvent,
and temperature effects on the overall yield for the reaction (Ta-
ble 1). First, we carried out a reaction in MeCN at 100 °C under
microwave irradiation for 20 min, but only trace amount of prod-
uct 10 was detected (in 20% yield, entry 1). The yield was increased
to 35% with a longer reaction time (entry 2). We further optimized
the reaction by varying the reaction solvents. When DMF was used
as solvent at 100 °C for 30 min, about 40% of product was isolated
(entry 4). Increasing the temperature from 100 °C to 120 °C in the
same solvent, the yield was slightly improved to 48% (entry 5). A
high yield of 80%, (entry 7) in DMF was obtained with a tempera-
ture of 160 °C. Interestingly, a good yield (75%, entry 10) was also
achieved with hexafluoro-2-propanol13 used as solvent under
more mild conditions (120 °C for 30 min).
With the optimized reaction condition in hand, we evaluated
the scope and limitations of the reaction. We initially assessed
the reactions of various substituted aminopyridines with 7 (Ta-
ble 2). As shown in Table 2, various aminopyridines were reacted
with 7 with DMF used as solvent at 160 °C for 30 min, and the cor-
responding substituted 2-(4-methoxyphenyl)imidazo[1,2-a]pyri-
din-3-ol were obtained in moderate to good yields.14 We also
found electron-rich pyridines gave higher yields than electron-
deficient pyridines. This was especially true with methyl substi-
tuted aminopyridines (entries 1–3), which afforded much higher
yields than aminopyridines with halide substituents (entries 5–7).
To further examine the efficiency of this reaction and to rapidly
expand our unique compound collection, reaction diversity was
Table 3
Substrate scope of phenylboronic acid
N
OH
MW
+
+
R
O
N
R
O
B(OH)2
N
NH2
OH
Entry
1
Boronic acid
Product
Yielda (%)
78b
O
N
B(OH)2
N
N
OH
O
O
O
B(OH)2
O
N
2
67b
OH
O
O
O
N
B(OH)2
O
3
4
5
6
69b
65b
61b
60b
N
N
N
N
OH
N
O
B(OH)2
OH
N
F3CO
B(OH)2
OCF3
OH
N
B(OH)2
OH
N
Cl
B(OH)2
Cl
Br
F
N
N
7
8
51c
55c
OH
N
Br
B(OH)2
B(OH)2
OH
N
F
F
9
54c
45c
N
N
OH
N
B(OH)2
10
F
OH
a
b
c
Isolated yield.
DMF, microwave, 160 °C, 30 min.
Hexafluoroisopropanol, microwave, 120 °C, 30 min.

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Y. Wang et al. / Tetrahedron Letters 55 (2014) 1281–1284
OH
OH
B
O
O
O
7
B
OH
O
OH
OH
OH
H
OH
OH
N
NH2
N
N
H
O
N
N
H
O
6
8
O
12
11
O
OH
B
OH
HO
OH
N
N
N
N
N
N
O
O
HO
HO
OH
OH
N
N
H
H2O
O
O
N
N
H
O
O
O
10
14
13
9
Scheme 3. Proposed mechanism for the reaction.
completed by varying the phenylboronic acid input. As demon-
strated in Table 3, with the same reaction conditions (DMF,
160 °C, 30 min), the reaction of phenylboronic acids containing
electron-donating groups with 6 underwent smoothly to afford
the corresponding products in good yields (entries 1–5). When
phenylboronic acid was used as substrate, a good yield (60%, entry
6) was also obtained. It is noteworthy that the reactivity of elec-
tron-deficient phenylboronic acids was slightly worse than elec-
tron-rich phenylboronic acids. The reaction of phenylboronic
acids containing electron-withdrawing groups with 6 produced
the desired products only in hexafluoroisopropanol. In hexafluoro-
isopropanol at 120 °C for 30 min, the reaction yield with the elec-
tron-deficient phenylboronic acids was optimized to 45–55%
(entries 7–10). Importantly, utilizing hexafluoroisopropanol as sol-
vent allows for significantly more mild conditions, which permits
the use of sensitive functional groups without sacrificing yield.
The plausible mechanistic pathway for the formation of 10
through three-component, one pot, domino reaction is depicted
in Scheme 3. Compound 9 was formed through the standard Peta-
sis reaction mechanism. Then compound 9 undergoes intramolec-
ular nucleophile cyclization followed by dehydroxylation and
aromatization to generate the thermodynamically stable com-
pound 10. To validate the proposed mechanism, we prepared com-
pound 9 and then converted it to compound 10. Under milder
reaction conditions (oil bath, 80 °C, DMF, 1 h), the three-compo-
nent Petasis reaction between 6, 7, and 8 proceeded smoothly
and compound 9 was isolated in 90% yield. Then compound 9
was dissolved in DMF (concentration 0.5 M) and irradiated under
microwaves (160 °C, 30 min), which resulted in an 89% isolated
yield of compound 10. Additionally, Follmann et al.10c reported
that the three-component reaction between 2-aminopyridine with
7 and 8 gave the normal Petasis reaction product 2-(4-methoxy-
phenyl)-2-(pyridin-2-ylamino)acetic acid.
Acknowledgment
We would like to thank The College of Pharmacy and The
University of Arizona for start-up funds.
References and notes
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Chem. 1998, 47, 107; (i) Bienayme, H.; Hulme, C.; Oddon, G.; Schmitt, P. Chem.
Eur. J. 2000, 6, 3321; (j) Lee, D.; Sello, J. K.; Schreiber, S. L. Org. Lett. 2000, 2, 709.
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A.; Zavialov, I. A. Tetrahedron 1997, 53, 16463.
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5. Naskar, D.; Roy, A.; Seibel, W. L.; Portlock, D. E. Tetrahedron Lett. 2003, 44, 5819.
6. Pyne, S. G.; Au, C. W. G.; Davis, A. S.; Morgan, I. R.; Ritthiwigrom, T.; Yazici, A.
Pure Appl. Chem. 2008, 80, 751.
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Kundu, B. Synlett 2007, 1591.
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14. Experimental procedure for the synthesis of 9: In a 10 mL microwave tube 2-
amino-5-methylpyridine (1 mmol), (4-methoxyphenyl)boronic acid (1 mmol),
and Glyoxylic acid (1 mmol, 50%) solution in water were taken in 5 mL DMF
and the tube was sealed with a pressure cap. The tube was irradiated in a CEM
Explorer microwave for 30 min at 160 °C. After cooling to room temperature,
the solvent was removed under vacuum to get the crude product, which is
purified by silica chromatography (DCM/MeOH = 10:1). Yellow solid (82%). 1H
NMR (400 MHz, DMSO-d6): d 8.04 (s, 1H), 7.89 (d, J = 8 Hz, 2H), 7.34 (d,
J = 12 Hz, 1H), 6.97 (d, J = 8 Hz, 2H), 6.92 (d, J = 8 Hz, 1H), 3.81 (s, 3H), 2.12 (s,
3H); 13C NMR (100 MHz, DMSO-d6): d 169.81, 168.20, 162.00, 161.45, 148.24,
148.19, 137.93, 130.65, 130.60, 129.48, 127.45, 115.14, 113.82, 55.84, 17.75;
LCMS: m/z = 255 [M+1]+.
In conclusion, we have developed an expeditious protocol
employing
a Petasis based cascade reaction to access imi-
dazo[1,2-a]pyridin-3-ol in a one pot operation in moderate to good
yields. In addition, low cost, availability of reagents, and high effi-
ciency in expanding molecule diversity make the developed meth-
odology operationally superior over existing protocols. Further,
efforts to screen the antifungal and anticancer activity of the syn-
thesized compounds are currently underway and will be reported
in due course. Studies are also in progress to utilize the functional-
ized imidazo[1,2-a]pyridin-3-ols for use as kinase inhibitors in
anticancer therapies.