Reaction of β-lactam carbenes with 2-pyridyl isonitriles: A one-pot synthesis of 2-carbonyl-3-(pyridylamino)imidazo[1,2-a]pyridines useful as fluorescent probes for mercury ion

Article abstract of DOI:10.1021/jo201273p

The one-pot reaction of β-lactam carbenes with 2-pyridyl isonitriles followed by an acidic hydrolysis was reported, which produced 2-carbonyl-3-(pyridylamino)imidazo[1,2-a]pyridines in moderate to good yields. Among the resulting novel imidazo[1,2-a]pyrid

Full text of DOI:10.1021/jo201273p

ARTICLE
pubs.acs.org/joc
Reaction of β-Lactam Carbenes with 2-Pyridyl Isonitriles: A One-Pot
Synthesis of 2-Carbonyl-3-(pyridylamino)imidazo[1,2-a]pyridines
Useful as Fluorescent Probes for Mercury Ion
Na Shao, Guang-Xian Pang, Cai-Xia Yan, Gao-Feng Shi, and Ying Cheng*
College of Chemistry, Beijing Normal University, Beijing 100875, China
S Supporting Information
b
ABSTRACT: The one-pot reaction of β-lactam carbenes with
2-pyridyl isonitriles followed by an acidic hydrolysis was re-
ported, which produced 2-carbonyl-3-(pyridylamino)imidazo-
[1,2-a]pyridines in moderate to good yields. Among the
resulting novel imidazo[1,2-a]pyridine derivatives, 1-(6-chloro-
3-(5-chloropyridin-2-ylamino)imidazo[1,2-a]pyridin-2-yl)-2-
ethylbutan-1-one was demonstrated to be an efficient fluores-
cent probe for mercury ion both in acetonitrile and in buffered
aqueous solution.
’ INTRODUCTION
remarkable biologic and optical properties, most of them were
derived from the structural modification of imidazo[1,2-a]-
pyridine compounds.22 The development of simple and efficient
methods for the direct construction of multifunctional imidazo-
[1,2-a]pyridines is still of high importance.
Imidazo[1,2-a]pyridines substituted by different functional
groups have attracted growing interest from both organic and
medicinal chemists owing to their diverse range of biologic and
pharmacological activities.1 For example, a series of imidazo[1,2-a]-
pyridine derivatives are inhibitors of PIKK, FGFR, Class I PI3
kinase, and protein serine/threonine kinase and therefore have
potential applications in the treatment of cancer.2 Some multi-
substituted imidazo[1,2-a]pyridines are inhibitors of histone
deacetylase,3 acetylcholinesterase,4 EphB3 kinase,5 and geranyl-
geranyl transferase,6 which may be utilized in the treatment of
proliferative disorders and Alzheimer's disease, provide neuro-
protection and repair of damaged neuronal tissue, and decrease
bone resorption by inhibiting farnesyl pyrophosphate synthase in
osteoclasts. Imidazo[1,2-a]pyridine derivatives also showed
antianxiety,7 antihepatitis C,8 antibacterium,9 antiinflammatory,10
and antiviral activity.11 Some imidazo[1,2-a]pyridine derivatives,
such as vasodilator olprinone,12 and hypnotics zolpidem and
alpidem,13 have been used as clinical medicines. Besides the
biologic activities, the optical properties constituted another
important feature of imidazo[1,2-a]pyridines.14 Fluorescent
imidazo[1,2-a]pyridine derivatives have been utilized as fluores-
cent dopamine D3 receptors ligands15 or as a fluorescent probe
for peripheral benzodiazepine receptors and microglial cell
visualization.16
In the 1990s, Warkentin and co-workers investigated the
reactions of 2-azetidinone-4-ylidenes, a type of β-lactam carbene
derived from thermolysis of spiro[β-lactam-4,20-oxadiazolines],23
with both electron-rich and electron-deficient alkenes or alkynes,
which formed β-lactam-spiro-cyclopropanes or β-lactam-spiro-
cyclopropenes. They demonstrated the β-lactam carbenes to be
ambiphilic carbenes but with pronounced electrophilic activity.24
In recent years, we have been interested in the development of
synthetic methods for the construction of novel spiro and fused
heterocyclic compounds from the reactions of β-lactam
carbenes.25ꢀ27 For example, we found that β-lactam carbenes
behaved as nucleophilic carbenes toward aryl isocyanates to form
β-lactam-spiro-indole derivatives.25 On the other hand, the elec-
trophilic reaction of β-lactam carbenes with phenyl isonitriles
produced 2-(4-azetidinonylidene)indoles 4 that rearranged into
δ-carbolin-2-ones 5 in the presence of an acid. A subsequent acidic
hydrolysis controllably converted δ-carbolin-2-ones 5 into two
types of fluorescent δ-carboline-2,4-diones 6 and 7 (Scheme 1).26
We envisioned that, by varying the structures of aryl isonitriles, the
reaction between β-lactam carbenes and aryl isonitriles might be
developed into a general method for the synthesis of aryl-fused
pyrrolo[3,2-b]pyridine compounds. To further explore the syn-
thetic utility of β-lactam carbenes, we undertook the current
investigation of the reaction of β-lactam carbenes with
2-pyridyl isonitriles. Instead of the formation of the expected
The construction of a imidazo[1,2-a]pyridine ring was gen-
erally based on the cyclocondensations of 2-aminopyridines with
α-halo ketones,17 α-halo acetaldehydes,11,18 or vinyl ether.19 The
three-component reactions of 2-aminopyridines with aldehydes
and isocyanides,20 or with aldehydes and terminal alkynes,21 are
also efficient methods for the preparation of imidazo[1,2-a]-
pyridine compounds. Although numerous syntheses of imidazo-
[1,2-a]pyridine derivatives have been reported because of their
Received: June 16, 2011
Published: August 08, 2011
r
2011 American Chemical Society
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ARTICLE
Scheme 1. Reaction of β-Lactam Carbenes 2 with Phenyl
1,4-dioxane, toluene, 1,1,2-trichloroethane, 3-pentanone, and
acetonitrile for 7ꢀ11 h. After the addition of 10 equiv of aqueous
HCl (12 M), the reaction mixture was refluxed for another 8ꢀ9 h.
From these reactions, product 10a was isolated in 12ꢀ69%
yields, among which the best result was obtained from the
reaction in dioxane. The reaction was then conducted in refluxing
1,4-dioxane followed by hydrolysis with different acids. To our
delight, the yield of 10a was improved to 84% while using
aqueous H2SO4 (12 M) to hydrolyze the reaction intermediate.
The generality of the reaction was studied in refluxing 1,4-
dioxane using spiro[β-lactam-4,20-oxadiazolines] 1 and 2-pyridyl
isonitriles 8, both bearing different substituents, under optimized
conditions. Because we have previously demonstrated that the
aryl groups attached to the nitrogen atom of β-lactam carbenes 2
have a negligible effect on the reaction of 2 with phenyl
isonitriles,26 and the products 10 yielded from the current
reaction did not contain the N-phenyl moiety of the carbenes,
we only varied the 3,3-dialkyl groups of carbenes 2 and the
substituents attached to the pyridyl of isonitriles 8. As indicated
in Table 2, although all reactions examined produced products
10 in moderate to good yields, the substituents of two reactants
did show some effects on the reaction. For example, when
different alkyl-substituted β-lactam carbenes, such as dimethyl-
2a, 3,3-diethyl- 2b, 3,3-cyclopentyl- 2c and 3,3-cyclohexyl-β-
lactam carbene 2d, reacted with a isonitrile 8, 3,3-dimethyl-β-
lactam carbene 2a produced a yield of product higher than
that of the others. On the other hand, while different isonitriles
including 2-pyridyl 8a, 2-(5-chloropyridyl) 8b, and 2-(6-
methylpyridyl) isonitrile 8c reacted with a carbene 2, the reaction
of 2-pyridyl isonitrile 8a afforded a yield of product higher than
that of 8b or 8c. The higher efficiency of 2a compared to 2bꢀd
can be explained by the smaller steric hindrance of methyl
compared to other alkyl groups in the reaction, while the lower
reactivity of isonitriles 8b and 8c compared to 8a was probably
due to the electronic or steric effects of substituents of 8. Because
isonitriles 8 acted as nucleophiles in this reaction, the electron-
withdrawing chlorine substituent might deactivate the nucleo-
philicity of 8b. The lower efficiency of 8c compared to 8a was
probably due to the steric hindrance of 6-methyl group of 8c in
the formation of the imidazo[1,2-a]pyridine ring (vide infra).
The products 10 were fully characterized by spectroscopic
data and microanalysis, which indicated that 10 were the adducts
of one β-lactam carbene 2 and two pyridyl isonitrile 8 with the
loss of PhN moieties of the carbenes. To identify the products
beyond doubt, the structure of 10a was also determined un-
ambiguously by single crystal X-ray diffraction analysis (see
Supporting Information).
Isonitriles 3.26
pyridopyrrolo[3,2-b]pyridine derivatives, the reaction produced
2-(4-azetidinonylidene)imidazo[1,2-a]pyridines that were
further converted into 2-carbonyl-3-(pyridylamino)imidazo[1,2-
a]pyridines by acidic hydrolysis. The resulting novel imidazo[1,2-
a]pyridine derivatives can be developed into efficient fluorescent
probes for mercury ion. Herein we report our results.
’ RESULTS AND DISCUSSION
Study of the Reaction of β-Lactam Carbenes with 2-Pyr-
idyl Isonitriles. In this work, β-lactam carbenes 2 are generated
in situ from thermolysis of spiro[β-lactam-4,20-oxadiazolines] 1,
which were prepared on the bases of Warkentin’s method23 and
our previous report.25 According to Warkentin’s reports and our
experiences, the optimal temperature for the generation of
β-lactam carbenes 2 from spiro-oxadiazolines 1 is around
100ꢀ110 °C.23ꢀ26 The reaction of 3,3-dimethyl-1-phenyl-2-
azetidinone-4-ylidene 2a with 1 equiv of 2-pyridyl isonitrile 8a
was initially carried out in refluxing 1,4-dioxane under nitrogen
atmosphere. It was found that the reaction of 2a with 8a
produced a yellow colored product 9a along with the dimer28
of 2-pyridyl isonitrile. However, pure 9a was not obtained,
because it partially converted into a fluorescent compound 10a
during chromatography and recrystallization. Because we have
known about the reaction of β-lactam carbenes with phenyl
isonitriles producing 2-(4-azetidinonylidene)indoles 4 that were
converted into δ-carbolinones 5, 6, or 7 by treatment with acid
(see Scheme 1),26 we initially guessed that the yellow colored
product 9a and fluorescent compound 10a derived from carbene
2a and 2-pyridyl isonitrile 8a, probably being the aza-analogues
of 2-(4-azetidinonylidene)indole 4 and δ-carbolinone 6 or 7,
respectively. However, after the analysis by single crystal X-ray
diffraction and spectroscopic methods, the structure of fluores-
cent compound 10a was determined to be 2-isobutyroyl-3-(2-
pyridylamino)imidazo[1,2-a]pyridine. In order to obtain the
stable product, the reaction of carbene 2a with 2-pyridyl isonitrile
8a followed by an acidic hydrolysis was carried out in a one-pot
procedure. Because product imidazo[1,2-a]pyridine 10a con-
tains two pyridine moieties, the reaction of carbene precursor 1a
with 2 equiv of 2-pyridyl isonitrile 8a was optimized by varying
solvents, reaction temperature, and the acids used for the
hydrolysis of intermediate 9a. As shown in Table 1, the
mixture of 1a with 8a was refluxed in different solvents including
To understand the mechanism for the formation of 2-carbo-
nyl-3-(pyridylamino)imidazo[1,2-a]pyridines 10 from the inter-
action of β-lactam carbenes 2 and pyridyl isonitriles 8, the
isolation and characterization of intermediates 9 were very
important. It was found that, although compounds 9 were
generally unstable during chromatography and recrystallization,
the products 9 derived from 3,3-diethyl-β-lactam carbene 2b
were more stable than those yielded from 3,3-dimethyl-β-lactam
carbene 2a. Thus, from the reaction of 2b with 8c, a small amount
of pure 9j was obtained, which was identified as 3,3-diethyl-4-(5-
methyl-3-(6-methyl-2-pyridylimino)imidazo[1,2-a]pyridin-2-
ylidene)-1-phenylazetidin-2-one by spectroscopic data. On the
basis of the structure of intermediate 9j and our knowledge of the
interaction pathway between β-lactam carbenes and phenyl
isonitriles 3 (see Scheme 1),26 the mechanism for the formation
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Table 1. Optimization of Reaction Conditions for the One-Pot Reaction of 3,3-Dimethyl-1-phenyl-β-lactam-4-ylidene 2a with
2-Pyridyl Isonitrile 8a Followed by an Acidic Hydrolysis
reaction conditions
entry
1a:8a
step 1
step 2
yield of 10a (%)
1
2
3
4
5
6
7
8
1:1
1:2
1:2
1:2
1:2
1:2
1:2
1:2
1,4-dioxane, reflux, 8 h
1,4-dioxane, reflux, 8 h
1,1,2-trichloroethane, 110 °C, 7 h
toluene, 110 °C, 8 h
3-pentanone, 110 °C, 10 h
CH3CN, reflux, 11 h
HCl (12 M), 1,4-dioxane, reflux, 8 h
HCl (12 M), 1,4-dioxane, reflux, 9 h
HCl (12 M), 1,1,2-trichloroethane, 110 °C, 9 h
HCl (12 M), toluene, 110 °C, 8 h
HCl (12M), 3-pentanone, 110 °C, 9 h
HCl (12 M), CH3CN, reflux, 9 h
39
69
12
61
46
31
84
75
1,4-dioxane, reflux, 9 h
1,4-dioxane, reflux, 9 h
H2SO4 (12 M), 1,4-dioxane, reflux, 9 h
TsOH (12 M), 1,4-dioxane, reflux, 9 h
Table 2. Reaction of Spiro[β-lactam-4,20-oxadiazolines] 1
and 2-Pyridyl Isonitriles 8 under Optimized Conditions
Scheme 2. Proposed Mechanism for the Formation of
Imidazo[1,2-a]pyridines 10 from the Reaction of Carbenes 2
with Isonitriles 8 Followed by Acidic Hydrolysis
entry
1
R1, R1
8
R2
yield of 10 (%)
1
1a
1b
1c
1d
1a
1b
1c
1d
1a
1b
1c
1d
Me, Me
Et, Et
8a
8a
8a
8a
8b
8b
8b
8b
8c
8c
8c
8c
H
10a: 84
10b: 71
10c: 61
10d: 76
10e: 63
10f: 54
10g: 41
10h: 46
10i: 66
10j: 62
10k: 58
10l: 63
2
H
3
(CH2)4
(CH2)5
Me, Me
Et, Et
H
4
H
5
5-Cl
5-Cl
5-Cl
5-Cl
6-Me
6-Me
6-Me
6-Me
6
7
(CH2)4
(CH2)5
Me, Me
Et, Et
8
9
10
11
12
(CH2)4
(CH2)5
of 2-carbonyl-3-(pyridylamino)imidazo[1,2-a]pyridines 10 from
the reaction of carbenes 2 with isonitriles 8 followed by acidic
hydrolysis was proposed in Scheme 2. The reaction was initiated
by coupling of the carbene with isonitrile to form a ketenimine
intermediate 11. Nucleophilic addition of the second isonitrile to
11 gave a dipolar intermediate 12. Intramolecular aromatic
electrophilic cyclization of imine cation of 12 to the nitrogen
atom of pyridine ring led to the formation of imidazo[1,2-a]-
pyridine derivative 9. Hydrolysis of the β-lactam moiety of 9
formed an acid intermediate 13. Aromatization of the dihydroi-
midazole ring of 13 by 1,5-H shift produced an imino-substituted
acid 14. The hydrolysis and decarboxylation of acid 14 in
strong acidic aqueous solution under heating afforded pro-
ducts 10.
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Figure 2. Changes in fluorescence emission spectra (λex = 351 nm) of
2.5 ꢁ 10ꢀ5 mol/L 10f upon additions of different concentrations of
Hg2+ in acetonitrile solution. The arrows indicate the signal changes as
the Hg2+concentrations are increased.
Figure 1. Fluorescent responses of 10aꢀl (2.5 ꢁ 10ꢀ5 M) to different
metal ions in acetonitrile solution. The excitation was at the maximum
absorption wavelength of each compound, and the emission was
recorded at the maximum emission wavelength. F0 and F are the
fluorescence intensity of relevant compound in the absence and
presence of metal ions, respectively. The concentration of metal ions
are all 3.6 ꢁ 10ꢀ5 M.
ions. Particularly, the fluorescence quenching value of 10f is
much larger than that of any other probes in the presence of Hg2+
(Figure 1).
The fluorescence spectra of 10f in the presence of different
concentrations of Hg2+ are shown in Figure 2. When 7.8 ꢁ 10ꢀ7
mol/L Hg2+ was added into 2.5 ꢁ 10ꢀ5 mol/L 10f in acetonitrile
medium, a slight decrease of the initial fluorescence could be
observed. In the concentration range from 1.7 ꢁ 10ꢀ6 mol/L to
2.0 ꢁ 10ꢀ5 mol/L, an obvious fluorescence decrease is observed.
At a higher Hg2+ concentration, more than 2.9 ꢁ 10ꢀ5 M, a total
quenching of the fluorescence emission is observed, which
reaches a plateau at about 0.94% of its initial intensity. The limit
of detection (LOD), defined as three times the standard devia-
tion of the blank solution, is calculated to be 8.0 ꢁ 10ꢀ8 mol/L
(α = 0.99). When titrated down to the clearly obvious change of
the probe fluorescence, the limit of detection for Hg2+ is
determined to be 1.7 ꢁ 10ꢀ6 mol/L.
Study of the Fluorescent Responses of 2-Carbonyl-
3-(pyridylamino)imidazo[1,2-a]pyridines 10 toward Metal
Ions. Because imidazo[1,2-a]pyridines 10 are fluorescent multi-
functional compounds that contain five heteroatoms in one
molecule, we envisioned that compounds 10 might be useful
ligands for certain metals and be utilized as fluorescent probes for
metal ions. Thus, the spectroscopic properties of 10 and their
fluorescent responses toward metal ions were investigated.
First, the UVꢀvisible and fluorescent spectroscopic properties
of imidazo[1,2-a]-pyridine derivatives 10aꢀl were studied in
acetonitrile and water, and the basic parameters are shown in
Table S1 in Supporting Information. The UVꢀvisible absorp-
tion, fluorescence excitation, and emission spectroscopy of
compounds 10 in acetonitrile are also shown in Figure S1 (see
Supporting Information). These compounds show maximum
absorption around 340 nm, and all of them are fluorescent,
displaying maximal emission wavelength ranging 410ꢀ490 nm in
the solvents studied. The quantum yields for compounds 10 are
listed in Table S2 (see Supporting Information). It was found
that the quantum yields of 10 are in the range of 1ꢀ3% in
acetonitrile and 0.1ꢀ0.5% in aqueous solution. All compounds
10 have higher quantum yields in acetonitrile than in water, and
10f has the highest quantum yield among these 12 compounds in
both solvents.
To explore the application of compounds 10 in the molecular
recognition, fluorescent responses of 10aꢀl to different metal
ions were examined, and the perchloric salts of Ag+, K+, Ca2+,
Cd2+, Co2+, Cu2+, Fe2+, Hg2+, Mg2+, Mn2+, Ni2+, and Pb2+ ions
were used. Considering the solubility of organic compounds 10
and inorganic metal ions, the titration experiments were first
conducted in acetonitrile solution. Figure 1 shows the fluorescent
quenching responses (F0/F) of 10aꢀl (2.5 ꢁ 10ꢀ5 mol/L) in
acetonitrile solution to different metal ions (3.6 ꢁ 10ꢀ5 mol/L),
where F0 and F are the fluorescence intensity of the fluorophore
at the maximal emission wavelength in the absence and presence
of metal ions. It can be seen clearly that each probe has a distinct
fluorescence quenching response to Hg2+ than to other metal
The absorption spectroscopic responses of 10f to different
concentrations of Hg2+ were also conducted in acetonitrile.
While the concentration of Hg2+ ranged from 4.95 ꢁ 10ꢀ7 to
1.75 ꢁ 10ꢀ4 M, the absorbance of probe 10f at 358 nm gradually
decreased and concomitantly a new rising absorption band
appeared at the range of 287ꢀ341 nm with an isosbestic point
at 341 nm (Figure 3).
It is important that a practical sensor can function in aqueous
medium. Because compounds 10 are organic bases, and the
interaction of 10 with mercury ion in aqueous solution might be
influenced by the acidity of the medium. The dependence of the
fluorescence changes of 10f on the pH in the absence and
presence of Hg2+ was examined. Titration experiments were
carried out by adding standard NaOH or HNO3 solution to an
aqueous solution of 10f (1.0 ꢁ 10ꢀ4 mol/L), or 10f and Hg2+. As
indicated in Figure 4, the fluorescence signal of 10f in the absence
of mercury ion is independent of pH in the range 4.5ꢀ9.5
(Figure 4, curve a). Curves b and c show the dependence of the
10f fluorescence response on pH to 2.0 ꢁ 10ꢀ6 and 2.0 ꢁ 10ꢀ5
mol/L mercury ion, respectively. The efficient pH range for
mercury ion detection is 5.0ꢀ9.0. At a pH value below 5.0, 10f
converted to its protonated form that reduces its ligation with
mercury ion. At higher pH, mercury ion may be complexed with
OHꢀ, which in turn reduces its complexation with probe 10f.
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Figure 6. Changes in fluorescence emission spectra (λex = 350 nm) of
1.0 ꢁ 10ꢀ4 mol/L 10f upon additions of different concentrations of
Hg2+ in Na2HPO4ꢀNaH2PO4 buffered aqueous solution. The arrows
indicate the signal changes as the Hg2+concentration is increased.
Figure 3. Changes in absorption spectra of 5 ꢁ 10ꢀ5 mol/L 10f upon
additions of different concentrations of Hg2+ in acetonitrile solution. The
arrows indicate the signal changes as the Hg2+concentrations are increased.
Figure 7. Response parameter value (α) is plotted as a function of the
logarithm of the Hg2+ concentration with different stoichiometric ratios
and association constants, and the experimental data (b) is fitted to
them. Fluorescence intensity was recorded at 476 nm with an excitation
wavelength of 351 nm in acetonitrile solution.
Figure 4. Fluorescence intensityꢀpH profiles for titrations of 10f
(2.5 ꢁ 10ꢀ5 mol/L) in 10% ethanolꢀwater solution: (a) in the absence
of Hg2+, (b) in the presence of 2.0 ꢁ 10ꢀ6 mol/L Hg2+, (c) in the
presence of 2.0 ꢁ 10ꢀ5 mol/L Hg2+. The excitation was at 351 nm, and
emission was recorded at 476 nm.
The spectroscopic response of 10f to different metal ions in
Na2HPO4ꢀNaH2PO4 buffer solution is shown in Figure 5. In
buffered aqueous solution, the fluorescence response of 10f to
Hg2+ presents excellent selectivity in comparison with other
heavy metal ions. Cu2+, Co2+, Mg2+, Ca2+, Fe2+, Mn2+, Pb2+, and
Ni2+ could hardly induce any change in the fluorescence spectra
of 10f even at a high concentration of 1.0 ꢁ 10ꢀ4 M, while Hg2+
could nearly quench the fluorescence of 1.0 ꢁ 10ꢀ4 mol/L 10f
completely. The fluorescence spectra of 10f in the presence of
different concentrations of Hg2+ are shown in Figure 6. The
addition of 9.90 ꢁ 10ꢀ8 mol/L Hg2+ to the buffered aqueous
solution of 1.0 ꢁ 10ꢀ4 mol/L 10f slightly induced the change of
the initial signal. The fluorescence intensity decreased gradually
upon addition of 2.94 ꢁ 10ꢀ7 to 1.72 ꢁ 10ꢀ4 mol/L Hg2+ to 10f
in buffered aqueous solution. In the concentration range from
2.94 ꢁ 10ꢀ7 mol/L to 8.30 ꢁ 10ꢀ6 mol/L, the changes in
fluorescence intensity are linear in relation to the concentration
of Hg2+. The limit of detection defined as three times the
standard deviation of the blank solution is calculated to be 1.0 ꢁ
10ꢀ7 mol/L (α = 0.99). When titrated down to the obvious
change in probe fluorescence, the limit of detection for Hg2+ is
determined to be 2.94 ꢁ 10ꢀ7 mol/L, which is comparable with
common Hg2+ fluorescent probes.29
Figure 5. Changes in fluorescence emission spectra (λex =350nm) of1.0ꢁ
10ꢀ4 mol/L 10f in Na2HPO4ꢀNaH2PO4 buffered aqueous solution upon
additions of various divalent metal ions at 1.0 ꢁ 10ꢀ4 mol/L.
Thus, Na2HPO4ꢀNaH2PO4 buffer was then selected as the
aqueous medium for the detection of mercury ion, and the pH
was set at 7.0.
To obtain more information about the binding interaction of
the probe with Hg2+, we performed fluorescent titrations in
acetonitrile, where the evolution of the fluorescence spectra of
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’ EXPERIMENTAL SECTION
General Procedure for the Reaction of β-Lactam Carbenes
with 2-Pyridyl Isonitriles. Under nitrogen atmosphere, a mixture of
spiro[β-lactam-4,20-oxadiazolines] 1 (1 mmol) and 2-pyridyl isonitriles
8 (2 mmol) in 1,4-dioxane (80 mL) was refluxed for 6ꢀ11 h. After the
reaction mixture was cooled, an aqueous solution of H2SO4 (12 M,
0.84 mL) was added, and then the mixture was refluxed for another
9ꢀ11 h. The reaction mixture was basified to pH ∼ 8ꢀ9, and the
solvents were removed under vacuum. The products 10 was isolated by
chromatography on a silica gel column, eluting with a mixture of
petroleum ether, ethyl acetate, and triethylamine from 20:2:1 to 10:2:1.
2-Methyl-1-(3-(pyridin-2-ylamino)imidazo[1,2-a]pyridin-
2-yl)propan-1-one 10a. 84%, mp 216ꢀ218 °C, IR ν (cmꢀ1) 3220,
3166, 1678, 1605, 1560; 1H NMR (400 MHz, CDCl3) δ (ppm) 8.24 (s,
1H), 8.14 (dd, J = 5.0, 1.0 Hz, 1H), 7.79 (d, J = 7.0 Hz, 1H), 7.56ꢀ7.62
(m, 2H), 7.22 (ddd, J = 9.2, 6.6, 1.2 Hz, 1H), 6.84 (ddd, J = 7.1, 5.0, 0.6
Hz, 1H), 6.74ꢀ6.78 (m, 2H), 3.90ꢀ3.97 (m, 1H), 1.27 (s, 3H), 1.25 (s,
3H); 13C NMR (100 MHz, CDCl3) δ (ppm) 201.2, 156.0, 147.5, 140.5,
137.8, 131.9, 126.2, 126.0, 124.9, 118.1, 115.1, 112.9, 109.7, 18.5; MS
(EI): 237 (100), 280 (M+, 15%). Anal. Calcd for C16H16N4O: C 68.55,
H 5.75, N 19.99; Found: C 68.44, H 5.62, N 19.82.
Figure 8. The proposed structure of a 2:1 complex of 10f with Hg2+.
10f was monitored as a function of the different amounts of Hg2+.
Supposing that the probe fluorescence quenching is the result of
the formation of a probe-to-Hg+2 complex in the ratio of m:n,
detailed examination of the fluorescence intensity changes at
476 nm as a function of Hg2+ concentration can determine the
stoichiometry m:n and the association constant K using a curve
fitting method.30,31 In Figure 7, the relative fluorescence intensity
value α, defined as the concentration of metal-complexed form of
10f to the initial concentration of the ligand, is given as a function
of the logarithm of Hg2+ concentration, lg C(Hg2+). The
experimental data points best fit the curve for a 2:1 probeꢀ
Hg2+ complex formation. The reasonable equilibrium constants
are lg K = 9.00 M2.
2-Ethyl-1-(3-(pyridin-2-ylamino)imidazo[1,2-a]pyridin-2-
yl)butan-1-one 10b. 71%, mp 128ꢀ130 °C, IR ν (cmꢀ1) 3231,
1
1668, 1604, 1558; H NMR (400 MHz, CDCl3) δ (ppm) 8.28 (br s,
1H), 8.14 (dq, J = 5.0, 1.0 Hz, 1H), 8.14 (dt, J = 7.0, 1.2 Hz, 1H), 8.14
(dt, J = 9.3, 1.0 Hz, 1H), 7.50 (ddd, J = 8.3, 7.3, 1.9 Hz, 1H), 7.14 (ddd,
J = 9.2, 6.6, 1.2 Hz, 1H), 6.76 (ddd, J = 7.2, 5.0, 0.8 Hz, 1H), 6.68 (dt, J =
6.8, 1.2 Hz, 2H), 3.65ꢀ3.72 (m, 1H), 1.70ꢀ1.77 (m, 2H), 1.53ꢀ1.60
(m, 2H), 0.81 (t, J = 7.4, 6H); 13C NMR (100 MHz, CDCl3) δ (ppm)
204.6, 154.9, 147.9, 140.9, 138.1, 131.0, 128.6, 126.1, 125.3, 119.0, 116.5,
112.1, 110.9, 49.6, 24.2, 11.6; MS (EI): 209 (100), 237 (90), 308 (M+,
80%). Anal. Calcd for C18H20N4O: C 70.11, H 6.54, N 18.17; Found:
C 69.89, H 6.74, N 17.87.
In addition, the mixture of 10f (2.5 ꢁ 10ꢀ5 mol/L) and Hg2+
(5.0 ꢁ 10ꢀ5 mol/L) in acetonitrile showed a peak of M =
953.1249 in the ESI mass spectrum, which was assigned to
[2(10f) + Hg2+ ꢀ H+] (calcd 953.1332), corroborating the
combination of the ligand with the metal ion (see Figure S3 in
Supporting Information). A possible structure of 10fꢀHg2+
complex is shown in Figure 8. The good correlation of the
measured data with the theoretical prediction confirms the
validity of the proposed method. We believe that the fluores-
cence intensity quenching of the probes by Hg2+ is contributed
by the proximity of the metal ion to the unpaired electrons of the
nitrogen atom of the ligand and subsequently results in the
intermolecular charge transfer (ICT) from the electron-rich
nitrogen atom to the electron-deficient metal center.32 The
ICT affords a dramatically reduced fluorescence as a function
of the Hg2+ concentration.
Cyclopentyl(3-(pyridin-2-ylamino)imidazo[1,2-a]pyridin-
2-yl)methanone 10c. 61%, mp 169ꢀ171 °C, IR ν (cmꢀ1) 3267,
1
1674, 1603, 1558; H NMR (400 MHz, CDCl3) δ (ppm) 8.17 (br s,
1H), 8.06 (dd, J = 5.0, 1.0 Hz, 1H), 7.72 (d, J = 7.0 Hz, 1H), 7.53 (d, J =
9.3 Hz, 1H), 7.49 (ddd, J = 8.4, 7.5, 1.8 Hz, 1H), 7.14 (ddd, J = 9.2, 6.6,
1.1 Hz, 1H), 6.76 (dd, J = 7.2, 5.1 Hz, 1H), 6.66ꢀ6.70 (m, 2H),
4.01ꢀ4.09 (m, 1H), 1.93ꢀ1.98 (m, 2H), 1.78ꢀ1.83 (m, 2H),
1.59ꢀ1.67 (m, 4H); 13C NMR (100 MHz, CDCl3) δ (ppm) 203.4,
154.9, 148.1, 141.0, 138.1, 130.5, 128.7, 126.1, 125.3, 118.9, 116.6, 112.1,
110.9, 47.2, 29.9, 26.3; MS (EI): 209 (80), 237 (100), 306 (M+, 40%).
Anal. Calcd for C18H18N4O: C 70.57, H 5.92, N 18.29; Found: C 70.57,
H 6.15, N 18.13.
’ CONCLUSION
Cyclohexyl(3-(pyridin-2-ylamino)imidazo[1,2-a]pyridin-
2-yl)methanone 10d. 76%, mp 154ꢀ156 °C, IR ν (cmꢀ1) 3194,
3133, 1673, 1599, 1585, 1562; 1H NMR (400 MHz, CDCl3) δ (ppm)
8.24 (br s, 1H), 8.06 (dt, J = 5.0, 0.7 Hz, 1H), 7.72 (d, J = 7.0 Hz, 1H),
7.54 (d, J = 9.3 Hz, 1H), 7.50 (ddd, J = 9.1, 7.4, 1.8 Hz, 1H), 7.14 (ddd,
J = 9.2, 6.6, 1.1 Hz, 1H), 6.76 (ddd, J = 7.2, 5.1, 0.7 Hz, 1H), 6.66ꢀ6.70
(m, 2H), 3.60ꢀ3.65 (m, 1H), 1.89ꢀ1.97 (m, 2H), 1.64ꢀ1.76 (m, 3H),
1.37ꢀ1.42 (m, 4H), 1.16ꢀ1.20 (m, 1H); 13C NMR (100 MHz, CDCl3)
δ (ppm) 204.0, 154.9, 148.0, 140.9, 138.1, 129.9, 129.0, 126.1, 125.3,
118.9, 116.5, 112.0, 110.9, 46.0, 28.8, 26.1, 25.6; HRMS (TOF-ESI):
321.1804 (M + 1), Anal. Calcd for C19H21N4O: 321.1715 (M + 1).
1-(6-Chloro-3-(5-chloropyridin-2-ylamino)imidazo[1,2-a]-
pyridin-2-yl)-2-methylpropan-1-one 10e. 63%, mp 166ꢀ168 °C,
IR ν (cmꢀ1) 3303, 1650, 1594, 1552; 1H NMR (400 MHz, CDCl3) δ
(ppm) 8.20 (s, 1H), 8.06 (d, J = 2.2 Hz, 1H), 7.76 (d, J = 1.2 Hz, 1H), 7.50
(ddd, J = 9.7, 5.2, 2.6 Hz, 1H), 7.14 (dd, J = 9.7, 2.0 Hz, 1H), 6.72 (d, J =
8.8 Hz, 1H), 3.76ꢀ3.87 (m, 1H), 1.18 (s, 3H), 1.16 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ (ppm) 204.5, 153.1, 146.5, 139.2, 138.2, 130.5,
In summary, we have studied the reaction of β-lactam
carbenes 2 with 2-pyridyl isonitriles 8. Being different from the
reaction of β-lactam carbenes with phenyl isonitriles that pro-
duced tricyclic δ-carbolinones in the presence of acidic catalyst,26
the reaction of β-lactam carbenes with 2-pyridyl isonitriles
followed by an acidic hydrolysis afforded bicyclic imidazo[1,2-a]-
pyridine derivatives in moderate to good yields. The resulting
novel imidazo[1,2-a]pyridine derivatives 10 have shown fluor-
escent responses to mercury ion. Among the different substituted
imidazo[1,2-a]pyridines 10 obtained in this work, 1-(6-chloro-
3-(5-chloropyridin-2-ylamino)imidazo[1,2-a]pyridin-2-yl)-2-
ethylbutan-1-one 10f has the most sensitive and selective re-
sponse to mercury. This work not only provided a simple and
efficient one-pot reaction for the construction of multifunctional
imidazo[1,2-a]pyridines that are not easy accessible by other
approaches but also demonstrated their application.
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The Journal of Organic Chemistry
ARTICLE
128.7, 127.3, 124.4, 123.7, 120.8, 119.2, 111.9, 36.5, 18.6; MS (EI): 305 (100),
307 (75), 348 (M+, 55%), 350 (35). Anal. Calcd for C16H14Cl2N4O:
C 55.03, H 4.04, N 16.04; Found: C 55.25, H 4.15, N 15.97.
J = 9.2, 6.8 Hz, 1H), 6.55 (d, J = 7.4 Hz, 1H), 6.44 (d, J = 6.8 Hz, 1H),
5.95 (d, J = 8.2 Hz, 1H), 3.97ꢀ4.06 (m, 1H), 2.60 (s, 3H), 2.26 (s, 3H),
1.85ꢀ1.93 (m, 2H), 1.70ꢀ1.76 (m, 2H), 1.55ꢀ1.63 (m, 4H); 13C NMR
(100 MHz, CDCl3) δ (ppm) 202.0, 158.4, 157.5, 143.1, 138.2, 137.4,
134.8, 127.5, 126.1, 117.0, 115.5, 114.5, 105.2, 47.5, 29.7, 26.3, 24.2,
18.9; MS (EI): 119 (90), 183 (87), 198 (95), 226 (100), 236 (95), 265
(85), 334 (M+, 84%). Anal. Calcd for C20H22N4O: C 71.83, H 6.63,
N 16.75; Found: C 71.57, H 7.01, N 16.71.
Cyclohexyl(5-methyl-3-(6-methylpyridin-2-ylamino)imidazo-
[1,2-a]pyridin-2-yl)methanone 10l. 63%, mp 165ꢀ167 °C, IR ν
(cmꢀ1) 3233, 3156, 1668, 1604, 1558; 1H NMR (400 MHz, CDCl3) δ
(ppm) 7.49 (d, J = 9.1 Hz, 1H), 7.31 (t, J = 7.8 Hz, 1H), 7.25 (s, 1H),
7.12 (dd, J = 9.2, 6.8 Hz, 1H), 6.61 (d, J = 7.4 Hz, 1H), 6.50 (dd, J = 6.7,
1.8 Hz, 1H), 5.99 (d, J = 8.1 Hz, 1H), 3.63ꢀ3.69 (m, 1H), 2.67 (s, 3H),
2.32 (s, 3H), 1.91ꢀ1.93 (m, 2H), 1.67ꢀ1.78 (m, 3H), 1.33ꢀ1.48 (m,
4H), 1.14ꢀ1.27 (m, 1H); 13C NMR (100 MHz, CDCl3) δ (ppm) 202.7,
158.4, 157.5, 143.0, 138.2, 137.3, 134.5, 127.7, 126.1, 117.0, 115.4, 114.5,
105.2, 46.3, 28.7, 26.0, 25.6, 24.2, 18.9; MS (EI): 237 (70), 241 (80), 348
(M+, 100%). Anal. Calcd for C21H24N4O: C 72.39, H 6.94, N 16.08;
Found: C 72.08, H 7.12, N 15.95.
3,3-Diethyl-4-(5-methyl-3-(6-methylpyridin-2-ylimino)-
imidazo[1,2-a]pyridin-2(3H)-ylidene)-1-phenylazetidin-2-
one 9j. 88%, mp 196ꢀ198 °C, IR ν (cmꢀ1) 1746, 1633, 1593, 1519,
1496; 1H NMR (400 MHz, CDCl3) (ppm) 7.45 (d, J = 6.6 Hz, 2H), 7.14
(t, J = 7.7 Hz, 2H), 6.99 (d, J = 9.0 Hz, 1H), 6.92 (tt, J = 7.4, 1.0 Hz, 1H),
6.86 (dd, J = 9.1, 6.8 Hz, 1H), 6.81 (dd, J = 9.1, 6.4 Hz, 1H), 6.62 (dd, J =
9.1, 1.0 Hz, 1H), 6.41 (dt, J = 6.8, 1.0 Hz, 1H), 5.98 (dd, J = 6.4, 0.6 Hz,
1H), 2.88 (s, 3H), 2.32 (s, 3H), 1.69ꢀ1.75 (m, 2H), 1.40ꢀ1.46 (m, 1H),
1.32ꢀ1.37 (m, 1H), 0.72 (t, J = 7.4 Hz, 3H), 0.43 (t, J = 7.5 Hz, 3H); 13C
NMR (100 MHz, CDCl3) (ppm) 171.1, 151.4, 144.4, 144.1, 140.1,
137.9, 133.8, 132.6, 129.8, 126.0, 124.9, 124.4, 121.7, 119.3, 116.3, 114.6,
112.7, 88.0, 76.0, 24.8, 21.6, 19.5, 8.7, 8.0; MS (EI): 92 (100), 339 (50),
394 (60), 437 (M+, 55%). Anal. Calcd for C27H27N5O: C 74.12, H 6.22,
N 16.01; Found: C 73.78, H 6.39, N 15.95.
1-(6-Chloro-3-(5-chloropyridin-2-ylamino)imidazo[1,2-a]-
pyridin-2-yl)-2-ethylbutan-1-one 10f. 54%, mp 119ꢀ121 °C, IR
ν (cmꢀ1) 3221, 3152, 1672, 1595, 1551; 1H NMR (400 MHz, CDCl3) δ
(ppm) 8.25 (s, 1H), 8.02 (d, J = 2.4 Hz, 1H), 7.76 (d, J = 1.1 Hz, 1H),
7.50 (ddd, J = 8.7, 6.3, 3.8 Hz, 1H), 7.13 (dd, J = 9.7, 2.0 Hz, 1H), 6.72 (d,
J = 8.7 Hz, 1H), 3.61ꢀ3.67 (m, 1H), 1.67ꢀ1.78 (m, 2H), 1.51ꢀ1.61 (m,
2H), 0.81 (t, J = 7.4 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ (ppm)
204.6, 153.0, 146.5, 139.2, 138.1, 131.7, 128.5, 127.1, 124.4, 123.7, 120.7,
119.4, 111.9, 49.7, 24.2, 11.6; MS (EI): 305 (100), 307 (70), 376 (M+,
40%), 377 (45), 378 (35), 379 (30). Anal. Calcd for C18H18Cl2N4O:
C 57.30, H 4.81, N 14.85; Found: C 57.15, H 5.06, N 14.81.
(6-Chloro-3-(5-chloropyridin-2-ylamino)imidazo[1,2-a]-
pyridin-2-yl)(cyclopentyl)methanone 10g. 41%, mp 159ꢀ161 °C,
1
IR ν (cmꢀ1) 3331, 1655, 1586, 1556; H NMR (400 MHz, CDCl3) δ
(ppm) 8.30 (s, 1H), 8.07 (d, J = 2.2 Hz, 1H), 7.80 (dd, J = 2.4, 0.7 Hz, 1H),
7.54 (ddd, J = 9.6, 5.5, 0.6 Hz, 1H), 7.17 (dd, J = 9.7, 2.0 Hz, 1H), 6.76 (d,
J = 8.8 Hz, 1H), 4.02ꢀ4.10 (m, 1H), 1.97ꢀ2.05 (m, 2H), 1.80ꢀ1.88 (m,
2H), 1.70ꢀ1.75 (m, 4H); 13C NMR (100 MHz, CDCl3) δ (ppm) 203.3,
153.0, 146.5, 139.3, 138.1, 131.2, 128.5, 127.2, 124.4, 123.7, 120.8, 119.3,
111.9, 47.3, 29.8, 26.3; MS (EI): 112 (100), 278 (65), 306 (60), 374 (M+,
55%), 376 (50). Anal. Calcd for C18H16Cl2N4O: C 57.61, H 4.30, N 14.93;
Found: C 57.66, H 4.55, N 14.91.
(6-Chloro-3-(5-chloropyridin-2-ylamino)imidazo[1,2-a]-
pyridin-2-yl)(cyclohexyl)methanone 10h. 46%, mp 171ꢀ173 °C,
IR ν (cmꢀ1) 3348, 3312, 1649, 1586, 1554; 1H NMR (400 MHz, CDCl3)
δ (ppm) 8.21 (s, 1H), 8.02 (d, J = 2.5 Hz, 1H), 7.74 (dd, J = 2.0, 0.8 Hz,
1H), 7.50 (ddd, J = 9.7, 3.6, 0.9 Hz, 2H), 7.11 (dd, J = 9.7, 2.0 Hz, 1H),
6.71 (d, J = 8.8 Hz, 1H), 3.55ꢀ3.62 (m, 1H), 1.90ꢀ1.95 (m, 2H),
1.61ꢀ1.76 (m, 3H), 1.41ꢀ1.45 (m, 4H), 1.32ꢀ1.40 (m, 1H); 13C NMR
(100 MHz, CDCl3) δ (ppm) 204.0, 153.0, 146.5, 139.2, 138.1, 130.7,
128.8, 127.1, 124.4, 123.8, 120.7, 119.3, 111.9, 46.1, 28.8, 26.0, 25.6; MS
(EI): 141 (100), 261 (70), 276 (90), 305 (90), 388 (M+, 75%), 390 (65).
Anal. Calcd for C19H18Cl2N4O: C 58.62, H 4.66, N 14.39; Found:
C 58.46, H 5.04, N 14.27.
’ ASSOCIATED CONTENT
S
Supporting Information. General procedure for the pre-
2-Methyl-1-(5-methyl-3-(6-methylpyridin-2-ylamino)imidazo-
[1,2-a]pyridin-2-yl)propan-1-one 10i. 66%, mp 170ꢀ172 °C,
IR ν (cmꢀ1) 3178, 1689, 1590, 1567; 1H NMR (400 MHz, CDCl3) δ
(ppm) 7.50 (d, J = 9.1 Hz, 1H), 7.34 (t, J = 7.8 Hz, 1H), 7.20 (br s, 1H),
7.14 (dd, J = 9.1, 6.8 Hz, 1H), 6.63 (d, J = 7.4 Hz, 1H), 6.51 (dd, J = 6.8,
0.9 Hz, 1H), 6.03 (d, J = 8.2 Hz, 1H), 3.85ꢀ3.96 (m, 1H), 2.68 (s, 3H),
2.35 (s, 3H), 1.20 (s, 3H), 1.18 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
(ppm) 203.3, 158.3, 157.3, 143.1, 138.3, 137.4, 134.2, 127.6, 126.2,
117.0, 115.5, 114.5, 105.3, 36.4, 24.1, 18.8, 18.6; MS (EI): 92 (100), 237
(65), 265 (45), 308 (M+, 60%). Anal. Calcd for C18H20N4O: C 70.11, H
6.54, N 18.17; Found: C 69.94, H 6.93, N 17.92.
b
paration of spiro[β-lactam-4,20-oxadiazolines] 1, spectroscopic
parameters (maximum absorption wavelength, maximum emis-
sion and excitation wavelength) and quantum yields of com-
pounds 10, mass spectra of 2:1 complex of 10f with Hg2+, the
method for Hg2+ detection, copies of H NMR and 13C NMR
1
spectra of products 10 and 9j, as well as single crystal data of 10a
(CIF). This material is available free of charge via the Internet at
http://pubs.acs.org.
’ AUTHOR INFORMATION
2-Ethyl-1-(5-methyl-3-(6-methylpyridin-2-ylamino)imidazo-
[1,2-a]pyridin-2-yl)butan-1-one 10j. 62%, mp 143ꢀ145 °C, IR ν
(cmꢀ1) 3273, 1673, 1597, 1579, 1560; 1H NMR (400 MHz, CDCl3) δ
(ppm) 7.39 (d, J = 9.1 Hz, 1H), 7.21(t, J = 7.8 Hz, 1H), 7.04 (br s, 1H),
7.02 (dd, J = 9.2, 6.8 Hz, 1H), 6.51 (d, J = 7.4 Hz, 1H), 6.39 (d, J = 6.8 Hz,
1H), 5.89 (d, J = 8.1 Hz, 1H), 3.58ꢀ3.65 (m, 1H), 2.56 (s, 3H), 2.24 (s,
3H), 1.57ꢀ1.68 (m, 2H), 1.40ꢀ1.50 (m, 2H), 0.70 (t, J = 7.4 Hz, 6H);
13C NMR (100 MHz, CDCl3) δ (ppm) 203.3, 158.4, 157.4, 143.0,
138.2, 137.3, 135.5, 127.4, 126.1, 117.1, 115.4, 114.5, 105.1, 49.7, 24.14,
24.06, 18.9, 11.5; MS (EI): 237 (55), 336 (M+, 100%), 337 (M + 1, 75).
Anal. Calcd for C20H24N4O: C 71.40, H 7.19, N 16.65; Found: C 71.42,
H 7.05, N 16.47.
Corresponding Author
*E-mail: ycheng2@bnu.edu.cn. Fax: +86-10-58805558.
’ ACKNOWLEDGMENT
This work was supported by the National Natural Science
Foundation of China (nos. 20832006 and 20972017 for Y.C.,
and no. 20905008 for N.S.), Beijing Municipal Commission of
Education, and the Fundamental Research Funds for the Central
Universities (2009SC-1).
Cyclopentyl(5-methyl-3-(6-methylpyridin-2-ylamino)imidazo-
[1,2-a]pyridin-2-yl)methanone 10k. 58%, mp 169ꢀ171 °C, IR ν
(cmꢀ1) 3179, 1685, 1590, 1559; 1H NMR (400 MHz, CDCl3) δ (ppm)
7.43 (d, J = 9.1 Hz, 1H), 7.26 (t, J = 7.8 Hz, 1H), 7.15 (s, 1H), 7.06 (dd,
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