α,β-Epoxy esters in multiple C-O/C-N bond-breaking/formation with 2-aminopyridines; Synthesis of biologically relevant (Z)-2- methyleneimidazo[1,2- a ]pyridin-3-ones

Article abstract of DOI:10.1055/s-0033-1339105

A new reaction of aryl 2,3-epoxy esters with 2-aminopyridines has been developed that involves multiple C-O/C-N bond-breaking/formation reactions in one chemical step. Compared with known reactions of α,β-epoxy esters, which take place through oxiranyl C-O or C-C bond cleavage, the present reaction exploits the tendency of the oxirane ring to act as a bi-electrophile. Thus, the reaction follows a unique cascade pathway of epoxide C-O bond cleavage, formation of an α-enamine ester, and intramolecular transamidation with chemo-, regio- and diastereoselectivity. The reaction allows access to biologically relevant (Z)-2-methyleneimidazo[1,2-a]pyridin-3-ones. Water and ethanol are the only by-products. The reaction is flexible, and aryl 2,3-epoxy esters as well as 2-aminopyridines possessing either electron-donating or -withdrawing functionalities, can be used. In contrast to various Bronsted and Lewis acid catalysts, polyphosphoric acid plays a multifunctional role in this intermolecular cascade reaction. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0033-1339105

1692▌
LETTER
lαet,teβr -Epoxy Esters in Multiple C–O/C–N Bond-Breaking/Formation with
2-Aminopyridines; Synthesis of Biologically Relevant (Z)-2-Methylene-
imidazo[1,2-a]pyridin-3-ones
Epoxy Esters in Cascade Reaction with 2-Aminopyridines
Sankar K. Guchhait,* Garima Priyadarshani, Neha Hura
Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research, S. A. S. Nagar, Sector 67, Mohali,
Punjab 160062, India
Fax +91(172)2214692; E-mail: skguchhait@niper.ac.in
Received: 04.03.2014; Accepted after revision: 09.04.2014
tively. Other significant applications of 2,3-epoxy es-
Abstract: A new reaction of aryl 2,3-epoxy esters with 2-amino-
ters/ketones include [3+2] heterocyclization for the
pyridines has been developed that involves multiple C–O/C–N
construction of quaternary imidazole skeletons,10 palladi-
bond-breaking/formation reactions in one chemical step. Compared
with known reactions of α,β-epoxy esters, which take place through
um(0)-catalyzed transformation into β-diketone,11 and
oxiranyl C–O or C–C bond cleavage, the present reaction exploits SmI2-mediated deoxygenation to produce the α,β-unsatu-
rated ester.12 Herein, we report a new reaction of aryl α,β-
epoxy esters with 2-aminopyridines that exploits the ten-
the tendency of the oxirane ring to act as a bi-electrophile. Thus, the
reaction follows a unique cascade pathway of epoxide C–O bond
cleavage, formation of an α-enamine ester, and intramolecular
dency of the oxirane ring to act as a bi-electrophile. The
transamidation with chemo-, regio- and diastereoselectivity. The re-
action allows access to biologically relevant (Z)-2-methyleneimid-
azo[1,2-a]pyridin-3-ones. Water and ethanol are the only by-
products. The reaction is flexible, and aryl 2,3-epoxy esters as well
as 2-aminopyridines possessing either electron-donating or -with-
drawing functionalities, can be used. In contrast to various Brønsted
and Lewis acid catalysts, polyphosphoric acid plays a multifunc-
tional role in this intermolecular cascade reaction.
reaction involves a cascade pathway of epoxide C–O bond
cleavage, formation of α-enamine ester, and intramolecu-
lar transamidation with chemo-, regio- and diastereoselec-
tivity. The approach allows access to biologically relevant
(Z)-2-methyleneimidazo[1,2-a]pyridin-3-one.
(Z)-2-Methyleneimidazo[1,2-a]pyridin-3-ones represent
a scaffold-hopped13 skeleton of aurones, which are a fla-
vonoid class of natural products that exhibit various
bioactivities14 including antitumor, antimicrobial, anti-in-
flammatory, antidiabetic and anti-Alzheimer’s activities,
and modulation of drug efflux.15 In addition, (Z)-2-meth-
ylene- and 3-keto-substituted imidazo[1,2-a]heterocycles
are important chromophore-substrates for biolumines-
cence in marine organisms.16 Consequently, the develop-
ment of efficient syntheses of these molecules is
considered valuable.
Key words: domino reactions, amino alcohols, epoxides, hetero-
cycles, fused-ring systems
Oxiranes are important building blocks in organic synthe-
sis because of their easy accessibility, their propensity for
opening of the strained ring, and because of their use in
the preparation of versatile organic motifs. Most ring-
opening reactions of oxiranes involve C–O bond cleav-
age, although C–C bond cleavage is also known. The cas-
cade reaction1 involving epoxide C–O bond cleavage in
the synthesis of polycyclic natural products is well
known.2 In the context of exploring the use of the oxirane
class of compounds for various reactions, the 2,3-epoxy
esters/ketones have attracted significant attention because
of their use as multifunctional substrates3 and because of
their ease of preparation.4 A remarkable example is the re-
action of glycidic ester with 2-aminothiophenol, which
provides 1,4-benzothiazepinone, a synthetic precursor of
calcium channel blocker drug diltiazem.5 Aryl oxiranyl-
carboxylates/ketones undergo interesting C–C bond het-
erolysis of the oxirane ring, generating carbonyl ylides6
that undergo dipolar cycloaddition with various π-sys-
tems. For example, the [3+2] cycloaddition of aryl oxira-
nyl-dicarboxylate/diketone/cyanoketone with indole,7
alkyne,8 or [60]fullerene9 furnishes furo[3,4-b]indole,
2,5-dihydrofuran, or C60-fused tetrahydrofuran, respec-
To develop reactions that can be used for the preparation
of bioactive natural flavonoid compounds, we considered
a new reaction of easily accessible α,β-epoxy esters and 2-
aminopyridine. Initial experiments with a model reaction
of ethyl 3-(4′-methoxyphenyl)oxirane-2-carboxylate and
2-aminopyridine were performed by using several Lewis
acid catalysts and conditions known for oxirane C–O
opening with amines.17 All of these conditions led to the
formation of inseparable mixtures of products, which
indicated multiple competing reactions.18 Catalysis by
p-TsOH produced a less complex mixture of products
from which one major product was isolated (Table 1, en-
try 1). Spectroscopic studies revealed that the product
was
(Z)-2-(4′-methoxybenzylidene)imidazo[1,2-a]-
pyridin-3-one. To check for consistency, the reaction of a
different epoxy ester 3-(4′-chlorophenyl)oxirane-2-car-
boxylate with 2-aminopyridine was performed to give 3a;
the reaction provided the same class of scaffold. The
structure was confirmed by X-ray diffraction study (Fig-
ure 1 and the Supporting Information).19
SYNLETT 2014, 25, 1692–1696
Advanced online publication: 23.05.2014
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DOI: 10.1055/s-0033-1339105; Art ID: st-2014-b0189-l
© Georg Thieme Verlag Stuttgart · New York

LETTER
Epoxy Esters in Cascade Reaction with 2-Aminopyridines
1693
Table 1 Optimization of the Reactiona
improve the yield of the product beyond 25%. The use of
HClO4 (entry 7) or AcOH (entry 9) resulted in the gener-
ation of more side reactions without formation of the de-
sired product. The use of MsOH–AcOH, Eaton’s reagent,
ZrCl4–Eaton’s reagent, poly(phosphoric acid) (PPA), or
ZrCl4–PPA under neat conditions, enhanced the product
yield substantially and PPA was found to be most effec-
tive (entry 14). Conducting the reaction with 1 equiv PPA
in MeCN resulted in reduced yield.
OMe
NH2
N
acid, solvent
N
+
temperature
N
O
H
EtO2C
O
OMe
We next examined on the generality of the developed re-
action with regard to both cascade partners. To our de-
light, various ethyl 3-aryloxirane-2-carboxylates and 2-
aminopyridines underwent the reaction (Table 2). Both
electron-withdrawing and electron-donating functional-
ities on the aryl of the epoxy ester as well as on the 2-ami-
nopyridines were compatible, although 3-(4′-nitro-
phenyl)oxirane-2-carboxylate provided less yield of prod-
uct 3j because of a lack of chemoselectivity. Unfortunate-
ly, conducting the reaction with the alkyl 2,3-epoxy ester,
ethyl 3-methyloxirane-2-carboxylate, gave a complex
product mixture that could not be separated. The tolerance
of the reaction towards functionalities such as chloro, bro-
mo, nitro, and methoxy groups provides the opportunity
for further chemical manipulations of the products.
Entry Acid (equiv)
Solvent Temp Time Yield
(°C) (h)b (%)c
1
2
3
4
5
6
7
p-TsOH (0.2)
p-TsOH (0.2)
p-TsOH (0.2)
p-TsOH (1)
TfOH (1)
toluene 110 18
DMF 110 18
12
9
DMSO 110 18
DMSO 110 18
16
23
20
25
NRd
22
NRd
43
35
42
46
62
DMSO 110
3
MsOH (1)
DMSO 110 14
HClO4 (1)
DMA
110 14
8e MsOH
–
–
–
–
–
110
110
110
110
110
110
110
110
1
1
1
1
1
1
1
9e AcOH
We were then curious to probe the transformations in-
volved in this reaction. Under the optimized conditions, a
few products other than imidazo[1,2-a]pyridinone 3 were
found to form in trace amounts. When the reaction of eth-
yl 3-(4′-chlorophenyl)oxirane-2-carboxylate with 2-ami-
nopyridine was carried out at lower temperature (60 °C),
an additional product was obtained, which was found to
be enamine ester (IV; Scheme 1). Upon treatment of this
isolated intermediate with PPA, imidazopyridinone 3 was
obtained in similar yield. In a different study, authentic
β-amino alcohol (I) was treated with PPA to also produce
imidazopyridinone 3 in similar yield. These results imply
that the reaction follows a cascade pathway involving
β-amino alcohol (I) and enamine ester (IV; path A,
Scheme 1). The 1,2-migration of the pyridinylamine moi-
ety in conversion of β-amino alcohol (I) into enamine
(IV) indicates the formation of a N-bridging ring, i.e.,
aziridine (II). In next step, rearrangement through C–N
opening of aziridine (II) and elimination, assisted by PPA
as nucleophilic catalyst20 and dual activator, for the for-
mation of enamine (IV) is quite possible (for diastereose-
lectivity in the pathway, see Scheme 2).
10e MsOH–AcOH (1:1)
11e MsOH–AcOH (1:2)
12e Eaton’s Reagent
13e ZrCl4 (0.05) + Eaton’s Reagent –
14f PPA
–
15f ZrCl4 (0.05) + PPA
16 PPA (1)
–
1.5 45
78 14 10
MeCN
a Substrates: 0.5 mmol each.
b Optimum time.
c Isolated yield.
d Poor conversion, and no desired product formed.
e 1 mL acid was used.
f 1.5 g PPA was used.
The results of the optimization study of the reaction are
summarized in Table 1. Various Brønsted acids (entries
1–7) with a range of concentrations and solvents did not
In normal acid-catalyzed epoxide C–O bond cleavage
with amine, the product β-amino alcohol does not undergo
further aziridination.17 Interestingly, in the PPA-promoted
reaction, β-amino alcohol (I) underwent aziridination
(path A) chemoselectively over trans-amidation of car-
boxyethyl with the ring NH of pyridin-2(1H)-imine
(path B). This signifies that aziridination of β-amino alco-
hol (I) occurred through dual activation of OH and NH by
PPA, which is not observed in usual methods, and, ulti-
mately, the oxirane of the epoxy ester served as a bi-elec-
trophile. The results of the optimization study together
with the physical properties of the acids, and the ineffec-
Figure 1 ORTEP structure of 3a19
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 1692–1696

1694
S. K. Guchhait et al.
LETTER
Table 2 Scope of the Reaction
PPA
110 °C
NH2
Ar
H
N
O
EtO2C
R
R
+
N
N
Ar
1–1.5 h
2
1
O
3
Variation in azine for reaction with β-(4-chlorophenyl)epoxy ester
Me
Ar
N
Ar
N
Ar
N
N
N
Me
N
O
O
O
3c, 65%
3a, 83%
3b, 77%
Br
Ar
Ar
N
N
Ar
N
N
N
Br
Cl
N
Br
O
O
O
3d, 82%
3e, 70%
3f, 38%
Variation in epoxy ester for reaction with 2-aminopyridine
F
Br
N
N
N
N
Cl
N
N
O
O
O
3h, 76%
3g, 73%
3i, 66%
NO2
Me
N
N
N
N
N
N
O
O
O
3k, 53%
3j, 40%
3l, 58%
NMe2
Naph
OMe
N
N
N
N
N
N
O
O
O
3n, 60%
3o, 68%
3m, 62%
tiveness of acids possessing non-nucleophilic counter-an- In conclusion, a new reaction of aryl α,β-epoxy esters with
ion (HClO4) or low acidity (AcOH) signify that PPA plays 2-aminopyridine derivatives mediated by poly(phosphor-
a crucial role in the present cascade reaction. The multi- ic acid) as a multifunctional activator, leads to biological-
functional behavior, Brønsted acidity, nucleophilic catal- ly relevant (Z)-2-methyleneimidazo[1,2-a]pyridin-3-one
ysis, dual activation, and polar protic solvent derivatives.21 In contrast to known reactions of α,β-epoxy
characteristics of PPA are critical features of this reagent. esters, which take place through oxiranyl C–O or C–C
bond cleavage, the present reaction involves the oxirane
Interestingly, the reaction involves several C–O/C–N
ring acting as a bi-electrophile in a cascade pathway of ep-
bond-breaking/making events in one chemical step and
oxide C–O bond-cleavage, formation of α-enamine ester,
proceeds with chemo-, regio-, and diastereoselectivity.
By-products were water and ethanol only. Considering
and intramolecular transamidation. The process takes
place with chemo-, regio- and diastereoselectivity. This
that five transformations take place, the yields of the prod-
work is expected to prompt further strategic use of α,β-ep-
ucts are very good to excellent.
Synlett 2014, 25, 1692–1696
© Georg Thieme Verlag Stuttgart · New York

LETTER
Epoxy Esters in Cascade Reaction with 2-Aminopyridines
1695
Ar
N
N
OH
O
Ar
path B
NH2
H
Ar
Ar
N
N
path A
HA/LA
O
N
+
CO2Et
N
N
EtO2C
OH
EtO2C
II
1
2
I
Ar
Ar
X
H
N
H
Ar
N
N
H
N
N
CO2Et
N
CO2Et
H
IV
X = OH or A (conjugate anion of HA/LA)
O
III
3
Scheme 1 Cascade pathway of the reaction
OH
Acknowledgment
NH2
Py
Nu
O
We gratefully acknowledge financial support from DST, New Delhi
for this investigation. N.H. is thankful to DST, New Delhi for her
DST-INSPIRE fellowship.
EtO2C
Ar
NHPy
H
H
CO2Et
H
CO2Et
H
H
Ar
Ar
H
N
Py
Supporting Information, with experimental details, cha-
racterization data (1H and 13C NMR spectra, xIR, HRMS, and
melting points) for products and intermediates, and X-ray cry-
stallographic data for product 3a (CCDC 959103), for this article
is available online at http://www.thieme-connect.com/pro-
ducts/ejournals/journal/ 10.1055/s-00000083.Supporting InformationSupporting Information
H
NHPy
NHPy
Nu
CO2Et
H
EtO2C
Nu
H
O
120°
CO2Et
Ar
60°
H
NHPy
H
Ar
H
Ar
H
References and Notes
E2 elimination
syn via E1cB
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HN
N
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H
Ar
CO2Et
CO2Et
Ar
H
H
N
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N
N
N
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H
O
O
(Z)
(E)
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O
O
O
P
Py =
Nu =
O
P
OH
N
OH
OH
n
Scheme 2 Diastereoselectivity in the cascade reaction
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oxy ester derivatives in the discovery of new organic com-
pounds and reactions. The convenient preparation of
imidazopyridinone derivatives by the developed method
will facilitate the use of this important class of compound
in organic synthesis and medicinal chemistry research.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 1692–1696

1696
S. K. Guchhait et al.
LETTER
3-(4′-chlorophenyl)oxirane-2-carboxylate (113 mg, 0.5
(11) Suzuki, M.; Watanabe, A.; Noyori, R. J. Am. Chem. Soc.
1980, 102, 2095.
mmol) in a round-bottom flask, was added PPA (1.5 g), and
the mixture was magnetically stirred at 110 °C under open
air. Upon completion of the reaction as indicated by TLC (1–
1.5 h), the resultant mixture was poured into crushed ice
(2 g) and neutralized with 5% aq NaOH. The mixture was
extracted with CH2Cl2 (2 × 25 mL) and the organic layer
was washed with brine (5 mL), dried over anhydrous
Na2SO4, and concentrated under reduced pressure. Column
chromatographic purification of the crude mass on silica gel
(EtOAc–hexane, 1:6) gave (Z)-2-(4-chlorobenzylidene)-2H-
imidazo[1,2-a]pyridin-3-one (3a; 106 mg, 83%) as a red
solid. Mp 182–184 °C; Rf = 0.33 (EtOAc–hexane, 10%).
Compounds 3a–o were prepared by following a similar
procedure.
(12) Concellón, J. M.; Bardales, E. Org. Lett. 2002, 4, 189.
(13) For scaffold-hopping strategies that have led to several
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T.; Schmid, G. Angew. Chem. Int. Ed. 1999, 38, 2894;
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(15) Hadjeri, M.; Barbier, M.; Ronot, X.; Mariotte, A. M.;
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Med. Chem. Lett. 1998, 8, 2919.
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44, 6025.
(18) This selectivity problem also arises because of constraints
commonly associated with epoxide ring opening by amines,
such as the formation of regioisomeric and undesired
products, incompatibility with less nucleophilic amines, and
the required use of an excess of amine.
Data for 3a: See Figure 2 for numbering. 1H NMR (400
MHz, CDCl3): δ = 8.16 (d, J = 8.3 Hz, 2 H, Hj), 7.62 (d, J =
6.8 Hz, 1 H, Ha), 7.40 (d, J = 8.3 Hz, 2 H, Hk), 7.23 (s, 1 H,
Hh), 7.17 (dd, J = 6.6, 9.2 Hz, 1 H, Hc), 6.93 (d, J = 9.4 Hz,
1 H, Hd), 6.25 (dd, J = 6.6, 6.6 Hz, 1 H, Hb); 13C NMR (100
MHz, CDCl3): δ = 167.4 (Cg), 156.7 (Ce), 138.6 (Cf), 137.9
(Cc), 136.4 (Ci), 133.7 (Cj), 133.2 (Cl), 129.1 (Ck), 127.2
(Ca), 126.0 (Cd), 119.3 (Cb), 109.3 (Ch); IR (neat): 2879,
1707, 1650, 1601 cm–1; HRMS (ESI): m/z [M(35Cl) + H]+
calcd. for C14H9ClN2O: 257.0481; found: 257.0477.
Cl
k
l
(19) CCDC 959103 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
from the Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
(20) So, Y. H.; Heeschen, J. P. J. Org. Chem. 1997, 62, 3552.
(21) Synthesis of (Z)-2-(4′-Chlorobenzylidene)-2H-imidazo-
[1,2-a]pyridin-3-one; Typical Procedure (Table 2): To a
mixture of 2-aminopyridine (47 mg, 0.5 mmol) and ethyl
j
k
d
e
N
c
f
j
i
h
g
N
b
H
a
O
Figure 2
Synlett 2014, 25, 1692–1696
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