Synthesis of imidazopyridines via copper-catalyzed, formal aza-[3 + 2] cycloaddition reaction of pyridine derivatives with α-diazo oxime ethers

Article abstract of DOI:10.1021/acs.joc.7b01714

The Cu-catalyzed, formal aza-[3 + 2] cycloaddition reaction of pyridine derivatives with α-diazo oxime ethers in trifluoroethanol was used to synthesize imidazopyridines via the release of molecular nitrogen and elimination of alcohol. These methods enabled modular synthesis of a wide range of N-heterobicyclic compounds such as imidazopyridazines, imidazopyrimidines, and imidazopyrazines with an α-imino Cu-carbenoid generated from the α-diazo oxime ethers and copper.

Full text of DOI:10.1021/acs.joc.7b01714

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Article
Synthesis of Imidazopyridines via Copper-Catalyzed, Formal Aza-[3 + 2]
Cycloaddition Reaction of Pyridine Derivatives with #-Diazo Oxime Ethers
Sangjune Park, Hyunseok Kim, Jeong-Yu Son, Kyusik Um,
Sooho Lee, Yonghyeon Baek, Boram Seo, and Phil Ho Lee
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b01714 • Publication Date (Web): 04 Sep 2017
Downloaded from http://pubs.acs.org on September 4, 2017
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Synthesis of Imidazopyridines via CopperꢀCatalyzed, Formal Azaꢀ[3 +
2] Cycloaddition Reaction of Pyridine Derivatives with αꢀDiazo Oxime
Ethers
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Sangjune Park,† Hyunseok Kim,† JeongꢀYu Son, Kyusik Um, Sooho Lee, Yonghyeon Baek, Boram
Seo and Phil Ho Lee*
Department of Chemistry, Kangwon National University, Chuncheon 24341, Republic of Korea
Eꢀmail: phlee@kangwon.ac.kr
Table of Contents
ABSTRACT: The Cuꢀcatalyzed, formal azaꢀ[3 + 2] cycloaddition reaction of pyridine derivatives
with αꢀdiazo oxime ethers in trifluoroethanol was used to synthesize imidazopyridines via the
release of molecular nitrogen and elimination of alcohol. These methods enabled modular synthesis
of a wide range of Nꢀheterobicyclic compounds such as imidazopyridazines, imidazopyrimidines,
and imidazopyrazines with an αꢀimino Cuꢀcarbenoid generated from the αꢀdiazo oxime ethers and
copper.
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■
INTRODUCTION
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NꢀContaining heterocyclic compounds are extremely important in the study of biological activity
and for pharmaceutical utilization.1 Especially, imidazopyridines with both pyridine and imidazole
moieties, which comprise a typical, privileged scaffold, exhibit antifungal properties and function as
antilipases, kinase inhibitors, and H1ꢀreceptor antagonists (Figure 1).2 For this reason, the
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development of a synthetic method for imidazopyridine and its derivatives from easily accessible
Figure 1. Medicinal Applications of Imidazopyridine Derivatives
compounds is needed. To date, the CBr4ꢀmediated, oxidative C−N bond formation reaction of 2ꢀ
aminopyridines with βꢀketo esters or 1,3ꢀdiones (a),3 Cu(II) and Fe(III) coꢀcatalyzed intermolecular
diamination of 2ꢀaminopyridines with alkynes (b),4 Cuꢀcatalyzed aerobic dehydrogenative
cyclization of pyridines with oxime esters (c),5 aromatic cyclization of MoritaꢀBaylisꢀHillman
acetates (MBHAs) with 2ꢀaminoꢀ1ꢀethoxycarbonylꢀmethylpyridium bromide (d),6 I2/CuOꢀpromoted
reaction of 2ꢀaminopyridines with ketones (e),7 and Auꢀcatalyzed reaction of 2ꢀaminopyridines with
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propionaldehydes (f)8 have been reported for the synthesis of imidazopyridines (Scheme 1).9 In
particular, it is very important to develop a useful modular method for the synthesis of a variety of
Nꢀheterobicyclic compounds containing an imidazole ring, such as imidazopyridines,
imidazopyridazines, imidazopyrimidines, imidazopyrazines, and imidazotriazines.
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Scheme 1. Previously Reported Synthetic Methods for Imidazopyridine
Recently, a wide range of synthetic methods have been reported for heterocyclic compounds
using a metal carbenoid derived from a diazo,10 triazole,11 and thiadiazole12 in the presence of a
transition metal catalyst. Encouraged by these results and interested in the potential utilities of Nꢀ
and Sꢀheterocyclic compounds in pharmaceuticals, we envisioned that if αꢀdiazo oxime ethers13
were treated with a variety of Nꢀheterocyclic compounds, including pyridine, pyridazine,
pyrimidine, pyrazine, and triazine, a large number of Nꢀheterobicyclic compounds containing the
imidazole ring would be produced through a formal azaꢀ[3 + 2] cycloaddition reaction together with
the release of molecular nitrogen and elimination of alcohol. Herein, we demonstrate an efficient
synthetic method for imidazopyridines via the Cuꢀcatalyzed, formal azaꢀ[3 + 2] cycloaddition
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reaction of pyridine derivatives with αꢀdiazo oxime ethers (Scheme 2). These methods enable the
modular synthesis of a wide range of Nꢀheterobicyclic compounds, such as imidazopyridine,
imidazopyridazine, imidazopyrimidine, and imidazopyrazine, bearing the imidazole moiety via an
αꢀimino Cuꢀcarbenoid generated from αꢀdiazo oxime ethers and copper.
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Scheme 2. Synthesis of Imidazopyridines from the Cuꢀcatalyzed, formal Azaꢀ[3 + 2]
Cycloaddition of Pyridine Derivatives with αꢀDiazo Oxime Ethers
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RESULTS and DISCUSSION
We initiated our studies with the reaction of pyridine (1a) with an αꢀdiazo oxime ether (2a) in the
presence of a copper catalyst (Table 1). When Cu(OAc)2 (5.0 mol %) was used in the reaction of 1a
with 2a in dichloroethane (DCE), the desired imidazopyridine (3a) was obtained in 3% yield with
4a (7%) (entry 1). The structure of 4a was confirmed by Xꢀray crystallography.14 Based on these
results, a variety of Cu catalysts, such as Cu(OTf)2, Cu(acac)2, Cu(tfacac)2, and Cu(hfacac)2, in
DCE were screened to determine that Cu(hfacac)2 (5.0 mol %) was the best catalyst, producing 3a
and 4a in 15% and 25% yields, respectively (entries 2ꢀ5). Further examination of the solvents
indicated that trifluoroethanol (TFE) was the optimum solvent, and the other solvents, such as
dioxane, acetonitrile, hexane, methanol, and ethanol, gave inferior results (entries 6ꢀ11). When TFE
was used as the solvent, the desired imidazopyridines, 3a and 3a’, were produced in 25% and 39%
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yields, respectively, along with 4a (4%) (entry 11). The imidazopyridine 3a’ bearing a
trifluoroethoxycarbonyl group was produced by the transesterification reaction of TFE with 3. In
this case, the imidazopyridines 3a and 3a’ were easily separated using column chromatography. The
best result was achieved via the treatment of 1a (0.2 mmol, 1.0 equiv) with 2a (2.0 equiv) using
Cu(hfacac)2 (5.0 mol %) in TFE at 80 °C for 3 h, which resulted in the imidazopyridines 3a and 3a’
in 43% and 55% yields, respectively (entry 12).
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Table 1. Reaction Optimizationa
entry
cat.
solvent
time (h)
yield (%)
3a 3a’ 4a
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Cu(OAc)2
DCE
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Cu(OTf)2
DCE
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Cu(acac)2
DCE
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Cu(tfacac)2
Cu(hfacac)2
Cu(hfacac)2
Cu(hfacac)2
Cu(hfacac)2
Cu(hfacac)2
Cu(hfacac)2
Cu(hfacac)2
Cu(hfacac)2
DCE
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DCE
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dioxane
MeCN
hexane
MeOH
EtOH
TFE
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12b,c
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25 39
43 55
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TFE
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in the solvent (2.0 mL) at 80 °C under N2 atmosphere. Yields were determined by NMR using
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CH2Br2 as an internal standard. bIsolated yield. c2a (0.4 mmol, 2.0 equiv) was used.
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After obtaining the optimum conditions, the scope and limitations of the formal azaꢀ[3 + 2]
cycloaddition reaction were investigated using a variety of αꢀdiazo oxime ethers (2) (Scheme 3).
When methyl and nꢀpentylꢀsubstituted αꢀdiazo oxime ethers were treated with pyridine in the
presence of Cu(hfacac)2 (5.0 mol %), the corresponding imidazopyridines 3b and 3c were obtained
in 96% and 77% yields, respectively. The αꢀdiazo oxime ether with a tertꢀbutoxycarbonyl group
also underwent the formal azaꢀ[3 + 2] cycloaddition reaction to produce 3d in 58% yield. Electronꢀ
donating groups, including 2ꢀ, 3ꢀ, and 4ꢀmethyl, 4ꢀmethoxy, and 3,4ꢀmethylenedioxy, on the phenyl
ring of the αꢀdiazo oxime ethers did not influence the efficiency of the reaction, and the
imidazopyridines 3eꢀ3i were obtained in good to excellent yields varying from 74% to 98%.
However, in the case of the 4ꢀmethoxyꢀ and 3,4ꢀmethylenedioxyꢀsubstituted αꢀdiazo oxime ethers,
the ethoxycarbonyl and trifluoroethoxycarbonyl imidazopyridines produced were unable to be
separated, and the mixtures of the Et and CH2CF3 ester are reported. A large number of electronꢀ
withdrawing groups, including chloroꢀ, bromoꢀ, nitroꢀ, and methoxycarbonylꢀ, on the phenyl ring
were well tolerated in the formal azaꢀ[3 + 2] cycloaddition reaction and afforded the desired
imidazopyridines (3j‘ꢀ3m) in good to excellent yields ranging from 78% to 89%. Although 2ꢀ
thiophenylꢀsubstituted αꢀdiazo oxime ether was less reactive, the desired imidazopyridine 3n was
obtained in an acceptable yield.
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Scheme 3. Scope of αꢀDiazo Oxime Ethersa
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aReaction conditions: 1a (0.2 mmol, 1.0 equiv), 2 (2.0 equiv), and Cu(hfacac)2 (5.0 mol %) were
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used in TFE at 80 C for 3 h under N2 atmosphere. Reaction was carried out at 90 C for 8 h. Et
and CH2CF3 esters are obtained as mixtures and NMR yields are reported.
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Next, a wide range of pyridine derivatives (1) were investigated in the formal azaꢀ[3 + 2]
cycloaddition reaction with αꢀdiazo oxime ethers (2) (Scheme 4). Electronic variation in the
substituents on the pyridine ring did not influence the reaction efficiency. 3ꢀMethylpyridine
underwent the Cuꢀcatalyzed cycloaddition reaction with αꢀdiazo oxime ether regioselectively at the
sterically hindered position to afford imidazopyridine 3o having methyl group on 8ꢀposition in 84%
yield. The structure of 3o was confirmed by Xꢀray crystallography.15 The electronꢀdonating 4ꢀ
methyl and 4ꢀethyl groups gave the desired imidazopyridines (3p, 3p’, 3q, and 3q’) in good yields.
The conditions of the Cuꢀcatalyzed formal azaꢀ[3 + 2] cycloaddition reaction were compatible with
bromoꢀ and iodoꢀgroups, and 3r and 3s were obtained in 78% and 75% yields, respectively. The
present method worked equally well with the electronꢀwithdrawing 4ꢀacetylꢀ and 4ꢀ
methoxycarbonylꢀsubstituted pyridines and led to the facile construction of imidazopyridines 3t
(95%) and 3u (68%) and 3u’ (26%). The tolerance of the bromo, iodo, ketone, and ester groups on
the pyridine ring is especially useful and provides an opportunity for further functional group
transformations. Quinoline underwent the Cuꢀcatalyzed cyclization reaction, producing the desired
imidazopyridine (3v) in 85% yield. Isoquinoline also provided the desired imidazopyridine (3w) in
81% yield. The reaction of 4ꢀphenylpyridine with the αꢀdiazo ethyl oxime ether gave the desired
imidazopyridines 3x (22%) and 3x’ (39%). Likewise, 4ꢀpꢀtolylpyridine and 4ꢀ(4ꢀ
chlorophenyl)pyridine were smoothly converted to the corresponding imidazopyridines in good
yields.
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Scheme 4. Scope of the Pyridinesa
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aReaction conditions: 1 (0.2 mmol, 1.0 equiv), 2 (2.0 equiv), and Cu(hfacac)2 (5.0 mol %) were used
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in TFE at 80 C for 3 h under N2 atmosphere. Reaction was carried out at 90 C for 8 h. Et and
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CH2CF3 esters are obtained as mixtures and NMR yields are reported.
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Next, we applied the present method to the synthesis of a variety of Nꢀheterobicyclic
compounds, including imidazopyridazines, imidazopyrimidines, imidazopyrazines, and
imidazotriazines, using pyridazines, pyrimidines, pyrazines, and triazines instead of pyridines in the
reaction with the αꢀdiazo oxime ether (Scheme 5). When pyridazine and 3ꢀmethylpyridazine were
treated with the αꢀdiazo oxime ether 2a in the presence of Cu(hfacac)2 (5.0 mol %), the formal azaꢀ
[3 + 2] cycloaddition reaction occurred, producing the corresponding imidazopyridazines 6a and 6b
in 80% and 96% yields, respectively. Pyrazine and 2,6ꢀdimethylpyrazine are applicable to the
present transformation and provided the corresponding imidazopyrazines 6d and 6f in 53% and
71% yields, respectively. It is noteworthy that 2ꢀmethylpyrazine is selectively cyclized to produce
6e in 59% yield. Although 4ꢀmethylpyrimidine was less reactive than pyridazine and pyrazine in the
cyclization reaction, the imidazopyrimidine 6c was obtained in an acceptable yield. However,
triazine was not efficient. The present method enabled modular synthesis of a wide range of Nꢀ
heterobicyclic compounds, such as imidazopyridines, imidazopyridazines, imidazopyrimidines, and
imidazopyrazines, bearing the imidazole moiety via an αꢀimino Cuꢀcarbenoid generated from αꢀ
diazo oxime ethers and copper.
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Scheme 5. Scope of the NꢀHeterocyclic Compounds in the Reaction with αꢀDiazo Oxime
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Ethera
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aReaction conditions: 5 (0.2 mmol, 1.0 equiv), 2a (2.0 equiv), and Cu(hfacac)2 (5.0 mol %) were
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used in TFE at 80 C for 3 h under N2 atmosphere. 5 (0.2 mmol, 1.0 equiv), 2a (2.0 equiv), and
Cu(hfacac)2 (10.0 mol %) were used in TFE for 12 h under N2 atmosphere.
The present method could be applied to the synthesis of Saripidem, which is an anxiolytic drug
(eq 1). Imidazopyridine 3j‘ was reduced via sodium borohydride in methanol and THF to produce
the corresponding alcohol in 93% yield.16 The reaction of alcohol with butyronitrile (Ritter
reaction)17 was followed by methylation and produced Saripidem in 75% yield.
Next, we examined the synthetic application of trifluoroethyl 2ꢀphenylimidazo[1,2ꢀa]pyridineꢀ3ꢀ
carboxylate (3a’) on C–H activation (Scheme 6). When 3a’ was treated with a tosyl azide in the
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presence of [Cp*IrCl2]2, AgPF6, and pivalic acid, the sulfonyl amidated imidazopyridine 7 was
obtained in 78% yield.18 Additionally, the Rhꢀcatalyzed C–H activation reaction of 3a’ with
dioxazolone produced the benzoylꢀamidated product ꢀ8 in 95% yield.19 The use of diazo Meldrum’s
acid in the presence of an iridium catalyst smoothly converted 3a’ to the ethoxycarbonyl methylated
imidazoꢀpyridine 9 in 80% yield.20 The Rhꢀcatalyzed alkenylation of 3a’ with ethyl acrylate was
successful and gave 10 in 86% yield.21
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Scheme 6. Applications of Imidazopyridine to C–H Activation
A plausible mechanism for the formation of the imidazopyridines (3) from the pyridine
derivatives (1) and αꢀdiazo oxime ethers (2) via Cuꢀcatalyzed, formal azaꢀ[3 + 2] cycloaddition is
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suggested in Scheme 7. First, the αꢀdiazo oxime ethers (2) were converted to a Cuꢀcarbenoid (I) in
the presence of the Cu catalyst, and this was accompanied by the release of molecular nitrogen.13
The nucleophilic addition of the nitrogen atom in the pyridine derivatives to the electrophilic
carbene center of I generates the copperꢀbound, zwitterionic intermediate II. Then, the anionic
copper of II releases an electron pair that flows into the Nꢀalkoxy imine moiety and makes the
nitrogen atom sufficiently nucleophilic to react with the cationic pyridinium to afford
dihydroimidazopyridine 4 and regenerate the copper(II) catalyst. Intermediate IIa is more favor
than IIb due to the steric hindrance and then, 3ꢀmethylpyridine, isoquinoline, and 2ꢀmethylpyrazine
underwent the Cuꢀcatalyzed cycloaddition reaction with αꢀdiazo oxime ether regioselectively at the
sterically hindered position. Finally, 4 is smoothly transformed to the imidazopyridine 3 through the
elimination of alcohol.
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Scheme 7. A Plausible Mechanism
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9
OR4
N
H
N
N
R2
R1
R2
R1
N
- R4OH
3
CO2R3
CO2R3
R2
O
4
N
R4O
OR3
[Cu]
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N2
2
N2
OR4
N
R1
R2
O
N
R2
[Cu]
N
OR3
R3O
O
R4O [Cu]
I
II
R1
1
N
R1
OR4
OR4
R2
N
N
N
R1
F
R2
N
Cu CO2R3
Cu CO2R3
O
F
F
O
O
F
O
F
F
CF3
CF3
IIa
IIb
disfavor
favor
■
CONCLUSION
In conclusion, we developed a Cuꢀcatalyzed, formal azaꢀ[3 + 2] cycloaddition reaction with
pyridine derivatives and αꢀdiazo oxime ethers in trifluoroethanol to synthesize imidazopyridines
with the release of molecular nitrogen and elimination of alcohol. This method enabled modular
synthesis of a wide range of Nꢀheterobicyclic compounds such as imidazopyridazines,
imidazopyrimidines, and imidazopyrazines.
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Experimental Section
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General: Reactions were carried out in ovenꢀdried glassware under a nitrogen atmosphere.
Cu(hfacac)2 were purchased and was used as received. Commercial available reagents were used
without purification. Trifluoroethanol was dried with CaH2. All reaction mixtures were stirred
magnetically and were monitored by thinꢀlayer chromatography using Silica gel preꢀcoated glass
plates, which were visualized with UV light and then developed using either iodine or a solution of
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anisaldehyde. Flash column chromatography was carried out using Silica gel (230ꢀ400 mesh). H
NMR (400 MHz) and 13C{1H} NMR (100 MHz) spectra were recorded on NMR spectrometer.
Deuterated chloroform was used as the solvent, and chemical shift values (δ) are reported in parts
1
per million relative to the residual signals of solvent [δ 7.26 for H (chloroformꢀd3) and δ 77.2 for
13C{1H} (chloroformꢀd3)]. Infrared spectra were recorded on FTꢀIR spectrometer as either a thin
neat pressed between two sodium chloride plates or as a solid suspended in a potassium bromide
disk. High resolution mass spectra (HRMS) were obtained by electron impact (EI) ionization
technique (magnetic sector ꢀ electric sector double focusing mass analyzer). Melting points were
determined in open capillary tube.
General Procedure for the Synthesis of αꢀdiazo oxime ether
To a solution of oxime ether (2.0 mmol) and 4ꢀmethylbenzenesulfonyl azide (1.2 equiv) in CH3CN
(4 mL) at 0 °C was added dropwise DBU (1.2 equiv). The resulting orange solution was stirred for
30 min at 0 °C and allowed to warm to room temperature. The reaction mixture was concentrated
and the crude material was purified by column chromatography to afford the desired diazo
compound. All procedures should routinely be carried out behind a safety shield in a fume hood.
General Procedure for the Synthesis of Imidazopyridines
Cu(hfacac)2 (5.0 mol %) and trifluoroethanol (1.0 mL) were added to an ovenꢀdried test tube
equipped with a stirring bar. To the solution was added αꢀdiazo oxime ether (0.4 mmol) in
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trifluoroethanol (1.0 mL) and then was added pyridine derivatives (0.2 mmol). The mixture was
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o
stirred at 80 C for 3 h. To remove Cu(hfacac)2, the residue was passed through a pad of Silica gel
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filter and eluted with CH2Cl2. The filtrate was concentrated under reduced pressure and the residue
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was purified by Silica gel flash column chromatography to give imidazopyridine
.
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Ethyl 2ꢀphenylimidazo[1,2ꢀa]pyridineꢀ3ꢀcarboxylate (3a): yield 22.9 mg (43%), white solid; mp
o
1
53−55 C; Rf = 0.2 (EtOAc:DCM:Hexane = 1:10:10); H NMR (400 MHz, CDCl3) δ 9.41 (td, J =
1.1 Hz, 7.0 Hz, 1H), 7.78ꢀ7.72 (m, 3H), 7.45ꢀ7.40 (m, 4H), 7.02 (dt, J = 1.2 Hz, 10.4 Hz, 1H), 4.30
(q, J = 7.1 Hz, 2H), 1.22 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 161.2, 153.7,
147.2, 134.6, 130.3, 128.8, 128.4, 128.0, 127.8, 127.6, 117.6, 114.2, 60.5, 14.1; IR (KBr) 3058,
2979, 2929, 1684, 1400, 1225, 1155, 1050 cmꢀ1; HRMS (EI) m/z: [M]+ Calcd for C16H14N2O2
266.1055, Found 266.1051.
2,2,2ꢀTrifluoroethyl 2ꢀphenylimidazo[1,2ꢀa]pyridineꢀ3ꢀcarboxylate (3a´): yield 35.2 mg (55%),
o
1
white solid; mp 99−101 C; Rf = 0.15 (EtOAc:DCM:Hexane = 1:10:10); H NMR (400 MHz,
CDCl3) δ 9.39 (td, J = 1.1 Hz, 7.0 Hz, 1H), 7.79 (td, J = 1.1 Hz, 9.0 Hz, 1H), 7.74ꢀ7.72 (m, 2H),
7.54ꢀ7.49 (m, 1H), 7.47ꢀ7.43 (m, 3H), 7.10 (dt, J = 1.3 Hz, 10.4 Hz, 1H), 4.62 (q, J = 8.4 Hz, 2H);
13C{1H} NMR (100 MHz, CDCl3) δ 159.0, 155.4, 147.8, 133.9, 130.0, 129.0, 128.8, 128.4, 128.0,
127.8, 122.9 (J = 277.6 Hz), 117.7, 114.7, 110.4, 59.8 (J = 36.9 Hz); 19F NMR δ ꢀ73.1 ppm; IR
(KBr) 3058, 2970, 1699, 1494, 1414, 1281, 1148 cmꢀ1; HRMS (EI) m/z: [M]+ Calcd for
C16H11F3N2O2 320.0773, Found 320.0773.
2,2,2ꢀTrifluoroethyl 2ꢀmethylimidazo[1,2ꢀa]pyridineꢀ3ꢀcarboxylate (3b): yield 49.6 mg (96%),
o
1
white solid; mp 100−102 C; Rf = 0.2 (EtOAc:DCM:Hexane = 1:10:10); H NMR (400 MHz,
CDCl3) δ 9.24 (d, J = 6.9 Hz, 1H), 7.66 (d, J = 8.9 Hz, 1H), 7.47ꢀ7.43 (m, 1H), 7.03 (dt, J = 1.0 Hz,
10.4 Hz, 1H), 4.76 (q, J = 8.4 Hz, 2H), 2.74 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 159.3,
19
154.7, 147.8, 128.6, 128.1, 123.3 (J = 277.2 Hz), 117.0, 114.4, 111.3, 60.0 (J = 36.7 Hz) 16.9; F
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NMR δ ꢀ73.7 ppm; IR (KBr) 3036, 2963, 2926, 1698, 1425, 1278, 1155 cmꢀ1; HRMS (EI) m/z: [M]+
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Calcd for C11H9F3N2O2 258.0616, Found 258.0613.
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2,2,2ꢀTrifluoroethyl 2ꢀpentylimidazo[1,2ꢀa]pyridineꢀ3ꢀcarboxylate (3c): yield 37.5 mg (77%),
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white solid; mp 71ꢀ73 °C; Rf = 0.3 (EtOAc:DCM:Hexane = 1:10:10); white solid; H NMR (400
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MHz, CDCl3)
δ 9.27 (dd, J = 0.7 Hz, 6.9 Hz, 1H), 7.68 (dd, J = 0.7 Hz, 8.9 Hz, 1H), 7.45 (t, J = 7.9
Hz, 1H), 7.04 (t, J = 6.9 Hz, 1H), 4.75 (q, J = 8.4 Hz, 2H), 3.09 (t, J = 7.9 Hz, 2H), 1.82ꢀ1.74 (m,
2H), 1.45ꢀ1.32 (m, 4H) 0.91 (t, J = 6.86 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3)
δ
159.3, 159.1,
148.0, 128.6, 128.2, 123.4 (J = 277.2 Hz), 117.2, 114.3, 110.8, 60.1 (J = 36.7 Hz), 32.0, 30.7, 29.5,
22.6, 14.1; 19F NMR δ ꢀ73.5 ppm; IR (KBr) 2959, 2923, 2861, 1702, 1415, 1335, 1278, 1170, 1080
cmꢀ1; HRMS (EI) m/z: [M]+ Calcd for C15H17F3N2O2 314.1242, Found 314.1239.
tertꢀButyl 2ꢀphenylimidazo[1,2ꢀa]pyridineꢀ3ꢀcarboxylate (3d): yield 34.2 mg (58%), colorless
1
oil; Rf = 0.3 (EtOAc:DCM:Hexane = 1:10:10); H NMR (400 MHz, CDCl3) δ 9.41 (td, J = 1.1 Hz,
7.0 Hz, 1H), 7.72ꢀ7.69 (m, 3H), 7.45ꢀ7.38 (m, 4H), 6.99 (dt, 1.2 Hz, 10.4 Hz, 1H), 1.43 (s. 9H);
13C{1H} NMR (100 MHz, CDCl3) δ 160.7, 153.2, 146.8, 135.0, 130.2, 128.4, 128.3, 127.6, 127.6,
117.5, 113.9, 113.2, 82.0, 28.3; IR (KBr) 3069, 2978, 2930, 1682, 1496, 1391, 1338, 1227, 1150
cmꢀ1; HRMS (EI) m/z: [M]+ Calcd for C18H18N2O2 294.1368, Found 294.1368.
2,2,2ꢀTrifluoroethyl 2ꢀ(oꢀtolyl)imidazo[1,2ꢀa]pyridineꢀ3ꢀcarboxylate (3e): yield 49.5 mg (74%),
colorless oil; Rf = 0.3 (EtOAc:DCM:Hexane = 1:20:20); 1H NMR (400 MHz, CDCl3) δ 9.37 (d, J =
6.9 Hz, 1H), 7.78 (d, J = 9.0 Hz, 1H), 7.55ꢀ7.50 (m, 1H), 7.34ꢀ7.21 (m, 4H), 7.13 (t, J = 10.4 Hz,
1H), 4.49 (q, J = 8.4 Hz, 2H), 2.21 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 159.1, 155.6, 147.9,
136.6, 134.2, 129.8, 129.6, 128.8, 128.7, 128.3, 125.2, 122.8 (J = 277.5 Hz), 117.9, 114.8,
111.6 ,59.9 (J = 36.9 Hz) 19.9; 19F NMR δ ꢀ73.8 ppm; IR (KBr) 3028, 2968, 2927, 1702, 1494,
1414, 1280, 1152 cmꢀ1; HRMS (EI) m/z: [M]+ Calcd for C17H13F3N2O2 334.0929, Found 334.0927.
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2,2,2ꢀTrifluoroethyl 2ꢀ(mꢀtolyl)imidazo[1,2ꢀa]pyridineꢀ3ꢀcarboxylate (3f): yield 65.8 mg (98%),
white solid; mp 75ꢀ77 oC; Rf = 0.3 (EtOAc:DCM:Hexane = 1:20:20); 1H NMR (400 MHz, CDCl3) δ
9.39 (td, J = 1.1 Hz, 7.0 Hz, 1H), 7.78 (td, J = 1.1 Hz, 8.9 Hz, 1H), 7.55ꢀ7.49 (m, 3H), 7.34 (t, J =
7.6 Hz, 1H), 7.25 (d, J = 7.0 Hz, 1H), 7.09 (dt, J = 1.3 Hz, 10.4 Hz, 1H), 4.62 (q, J = 8.5 Hz, 2H),
2.41 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 159.3, 155.7, 148.0, 137.6, 133.9, 130.7, 129.9,
128.9, 128.6, 127.8, 127.3, 123.1 (J = 277.5 Hz), 117.8, 114.8, 110.4, 59.9 (J = 36.9 Hz), 21.4; 19F
NMR δ ꢀ73.1 ppm; IR (KBr) 3054, 2978, 2930, 1685, 1496, 1384, 1227, 1150 cmꢀ1; HRMS (EI)
m/z: [M]+ Calcd for C17H13F3N2O2 334.0929, Found 334.0930.
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Ethyl 2ꢀ(pꢀtolyl)imidazo[1,2ꢀa]pyridineꢀ3ꢀcarboxylate (3g):23 yield 11.8 mg (21%), white solid;
o
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mp 86ꢀ88 C; Rf = 0.3 (EtOAc:DCM:Hexane = 1:20:20); H NMR (400 MHz, CDCl3) δ 9.41 (td, J
= 1.1, 7.0 Hz, 1H), 7.73 (td, J = 1.1 Hz, 8.9 Hz, 1H), 7.68 (dd, J = 1.7 Hz, 6.4 Hz, 2H), 7.45ꢀ7.40
(m, 1H), 7.24 (dd, J = 0.6 Hz, 8.5 Hz, 2H), 7.02 (dt, J = 1.3 Hz, 10.4 Hz, 1H), 4.33 (q, J = 7.1 Hz,
2H), 2.42 (s, 3H), 1.26 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 161.4, 153.9, 147.2,
138.7, 131.6, 130.2, 128.5, 128.4, 127.9, 117.6, 114.0, 111.9, 60.5, 21.5, 14.2
2,2,2ꢀTrifluoroethyl 2ꢀ(pꢀtolyl)imidazo[1,2ꢀa]pyridineꢀ3ꢀcarboxylate (3g´): yield 42.1 mg (63%),
o
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white solid; mp 154ꢀ157 C; Rf = 0.35 (EtOAc:DCM:Hexane = 1:20:20); H NMR (400 MHz,
´CDCl3) δ 9.37 (d, J = 7.0 Hz, 1H), 7.77 (d, J = 8.9 Hz, 1H), 7.65 (d, J= 8.1 Hz, 2H), 7.52ꢀ7.48 (m,
1H), 7.25 (d, J = 6.5 Hz, 2H), 7.09 (dt, J = 1.2 Hz, 10.4 Hz, 1H), 4.63 (q, J = 8.5 Hz, 2H), 2.42 (s,
3H); 13C{1H} NMR (100 MHz, CDCl3) δ 159.2, 155.7, 148.0, 139.1, 131.0, 130.1, 128.8, 128.6,
123.1 (J = 277.8Hz), 117.8, 114.7, 110.4, 59.8 (J = 36.9 Hz), 21.5; 19F NMR δ ꢀ73.0 ppm; IR (KBr)
2980, 2924, 1683, 1497, 1404, 1336, 1223, 1155 cmꢀ1; HRMS (EI) m/z: [M]+ Calcd for
C17H13F3N2O2 334.0929, Found 334.0930.
Ethyl 2ꢀ(4ꢀmethoxyphenyl)imidazo[1,2ꢀa]pyridineꢀ3ꢀcarboxylate (3h, minor): NMR yield 8%,
1
white solid; Rf = 0.3 (EtOAc:DCM:Hexane = 1:20:20); H NMR (400 MHz, CDCl3) δ 9.40 (d, J =
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7.0 Hz, 1H), 7.76ꢀ7.70 (m, 3H), 7.43ꢀ7.39 (m, 1H), 7.02ꢀ7.00 (m, 1H), 7.00ꢀ6.95 (m, 2H), 4.33 (q, J
= 7.1 Hz, 2H), 3.87 (s, 3H), 1.27 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 161.4,
160.2, 153.6, 131.8, 128.5, 128.0, 127.0, 117.4, 114.0, 113.4, 60.5, 14.3; IR (KBr) 2967, 2839, 1697,
1612, 1484, 1417, 1387, 1281, 1250, 1176 cmꢀ1; HRMS (EI) m/z: [M]+ Calcd for C17H16N2O3
296.1161, Found 296.1162.
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2,2,2ꢀTrifluoroethyl 2ꢀ(4ꢀmethoxyphenyl)imidazo[1,2ꢀa]pyridineꢀ3ꢀcarboxylate (3h‘, major):
1
NMR yield 81%, white solid; Rf = 0.3 (EtOAc:DCM:Hexane = 1:20:20); H NMR (400 MHz,
CDCl3) δ 9.36 (d, J = 7.0 Hz, 1H), 7.72 (dd, J = 2.1 Hz, J = 6.8 Hz, 1H), 7.51ꢀ7.47 (m, 1H), 7.07
(dd, J = 1.1 Hz, 10.4 Hz, 1H), 6.98(dd, J = 2.1 Hz, J = 6.8 Hz 2H), 4.64 (q, J = 8.5 Hz, 2H), 3.87 (s,
3H); 13C{1H} NMR (100 MHz, CDCl3) δ 160.5, 159.2, 155.4, 148.0, 131.6, 128.9, 128.6, 126.3,
123.1 (J = 277.7 Hz), 117.7, 114.6, 113.4, 110.1, 59.9 (J = 36.9 Hz), 55.5; 19F NMR δ ꢀ73.0 ppm;
IR (KBr) 2967, 2839, 1697, 1612, 1484, 1417, 1387, 1281, 1250, 1176 cmꢀ1; HRMS (EI) m/z: [M]+
Calcd for C17H13F3N2O3 350.0878, Found 350.0880.
Ethyl 2ꢀ(benzo[d][1,3]dioxolꢀ5ꢀyl)imidazo[1,2ꢀa]pyridineꢀ3ꢀcarboxylate (3i, minor): NMR yield
33%, white solid; Rf = 0.2 (EtOAc:DCM:Hexane = 1:3:3); 1H NMR (400 MHz, CDCl3) δ 9.39 (td, J
= 1.1 Hz, 7.0 Hz, 1H), 7.70 (td, J = 1.1 Hz, 9.0 Hz, 1H), 7.43ꢀ7.39 (m, 1H), 7.34ꢀ7.23 (m, 2H), 7.00
(dt, J = 1.3 Hz, 10.4 Hz, 1H), 6.90 (d, J = 8.0 Hz, 1H), 6.01 (s, 2H), 4.34 (q, J = 7.1 Hz, 2H), 1.27 (t,
J = 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 161.1, 159.0, 155.1, 153.2, 148.5, 148.1,
147.8, 147.3, 147.0, 128.9, 128.5, 128.4, 128.3, 128.0, 127.7, 124.5, 123.1 (J = 277.6 Hz), 117.6,
117.7, 114.4, 114.0, 111.7, 110.9, 110.6, 110.2, 107.9, 107.7, 101.30, 101.26, 101.2, 60.5, 59.9 (J =
36.8 Hz), 14.1; IR (KBr) 3051, 2978, 2898, 1696, 1472, 1394, 1342, 1242, 1170, 1040 cmꢀ1; HRMS
(EI) m/z: [M]+ Calcd for C17H14N2O4 310.0954, Found 310.0953.
2,2,2ꢀTrifluoroethyl 2ꢀ(benzo[d][1,3]dioxolꢀ5ꢀyl)imidazo[1,2ꢀa]pyridineꢀ3ꢀcarboxylate (3i‘,
major): NMR yield 50%, white solid; Rf = 0.2 (EtOAc:DCM:Hexane = 1:3:3); 1H NMR (400 MHz,
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CDCl3) δ 9.34 (td, J = 1.1 Hz, 7.0 Hz, 1H), 7.73 (td, J = 1.1 Hz, 9.0 Hz, 1H), 7.50ꢀ7.46 (m, 1H),
7.34ꢀ7.23 (m, 2H), 7.06 (dt, J = 1.2 Hz, 10.4 Hz, 1H), 6.90 (d, J = 8.1 Hz, 1H), 5.99 (s, 2H), 4.65 (q,
J = 8.5 Hz, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 161.1, 159.0, 155.1, 153.2, 148.5, 148.1,
147.8, 147.3, 147.0, 128.9, 128.5, 128.4, 128.3, 128.0, 127.7, 124.5, 123.1 (J = 277.6 Hz), 117.6,
117.7, 114.4, 114.0, 111.7, 110.9, 110.6, 110.2, 107.9, 107.7, 101.30, 101.26, 101.2, 60.5, 59.9 (J =
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36.8 Hz), 14.1; F NMR δ ꢀ73.1 ppm; IR (KBr) 3051, 2978, 2898, 1696, 1472, 1394, 1342, 1242,
1170, 1040 cmꢀ1; HRMS (EI) m/z: [M]+ Calcd for C17H11F3N2O4 364.0671, Found 364.0671.
2,2,2ꢀTrifluoroethyl 2ꢀ(4ꢀchlorophenyl)imidazo[1,2ꢀa]pyridineꢀ3ꢀcarboxylate (3j‘): yield 63.3
o
1
mg (89%), white solid; mp 118ꢀ120 C; Rf = 0.3 (EtOAc:DCM:Hexane = 1:20:20); H NMR (400
MHz, CDCl3) δ 9.38 (d, J = 7.0 Hz, 1H), 7.78 (d, 9.0 Hz 1H), 7.69 (dd, J = 1.9 Hz, 6.6 Hz, 2H),
7.55ꢀ7.51 (m, 1H), 7.43 (dd, J = 1.9 Hz, 6.7 Hz, 2H), 7.12 (dt, J = 1.1 Hz, 10.4 Hz, 1H), 4.63 (q, J =
8.4 Hz, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 159.0, 154.3, 148.0, 135.3, 132.5, 131.5, 129.2,
128.6, 128.2, 123.0 (J = 277.6 Hz), 117.9, 115.0, 110.6, 60.0 (J = 36.9 Hz); 19F NMR δ ꢀ73.1 ppm;
IR (KBr) 2970, 2917, 1700, 1409, 1384, 1336, 1280, 1147 cmꢀ1; HRMS (EI) m/z: [M]+ Calcd for
C16H10ClF3N2O2 354.0383, Found 354.0386.
tertꢀButyl 2ꢀ(3ꢀbromophenyl)imidazo[1,2ꢀa]pyridineꢀ3ꢀcarboxylate (3k): yield 66.4 mg (89%),
colorless oil; Rf = 0.4 (EtOAc:DCM:Hexane = 1:10:10); 1H NMR (400 MHz, CDCl3) δ 9.42 (td, J =
1.1 Hz, 7.0 Hz, 1H), 7.86 (t, J = 1.7 Hz, 1H), 7.72 (td, J = 1.0 Hz, 8.9 Hz, 1H), 7.68 (td, J = 1.3 Hz,
7.7 Hz, 1H), 7.53 (qd, J = 1.0 Hz, 8.0 Hz, 1H), 7.45ꢀ7.41 (m, 1H) 7.31 (t, J = 7.9 Hz, 1H), 7.02 (dt,
J = 1.2 Hz, 10.4 Hz, 1H), 1.47 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3) δ 160.5, 151.3, 146.9,
137.1, 133.5, 131.4, 129.3, 128.8, 128.4, 128.0, 121.5, 117.6, 114.2, 113.3, 82.3, 28.4; IR (KBr)
2978, 2930, 1684, 1496, 1384, 1227, 1150 cmꢀ1; HRMS (EI) m/z: [M]+ Calcd for C18H1779BrN2O2
372.0473, C18H1781BrN2O2, 374.0455 Found 372.0470, 374.0461.
Ethyl 2ꢀ(4ꢀnitrophenyl)imidazo[1,2ꢀa]pyridineꢀ3ꢀcarboxylate (3l): yield 37.4 mg (60%), white
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solid; mp 174ꢀ176 oC; Rf = 0.15 (EtOAc:Hexane = 1:5); 1H NMR (400 MHz, CDCl3) δ 9.43 (td, J =
1.1 Hz, 7.0 Hz, 1H), 8.31 (dd, J = 2.0 Hz, 6.9 Hz, 2H), 7.97 (dd, J = 2.0 Hz, 6.9 Hz, 2H), 7.77 (td, J
= 1.1 Hz, 9.0 Hz, 1H), 7.52ꢀ7.48 (m, 1H), 7.10 (dt, J = 1.2 Hz, 10.4 Hz, 1H), 4.35 (q, J = 7.1 Hz,
2H), 1.25 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 160.6, 150.9, 148.0, 147.4, 141.2,
131.4, 128.6, 128.5, 122.9, 117.9, 114.8, 112.7, 61.0, 14.2; IR (KBr) 2997, 2918, 1687, 1516, 1380,
1344, 1225, 1169 cmꢀ1; HRMS (EI) m/z: [M]+ Calcd for C16H13N3O4 311.0906 Found 311.0904.
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Ethyl 2ꢀ(4ꢀmethoxyphenyl)imidazo[1,2ꢀa]pyridineꢀ3ꢀcarboxylate (3m): NMR yield 41%, white
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solid; Rf = 0.3 (EtOAc:DCM:Hexane = 1:20:20); H NMR (400 MHz, CDCl3) δ 9.43 (dd, J = 0.9
Hz, J = 7.0 Hz, 1H), 8.12ꢀ8.11 (m, 2H), 7.80ꢀ7.74 (m, 3H), 7.48ꢀ7.44 (m, 1H), 7.13 (t, J = 6.9 Hz,
1H), 4.31 (q, J = 7.1 Hz, 2H), 3.96 (s, 3H), 1.22 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (100 MHz,
CDCl3) δ 161.4, 160.2, 153.6, 131.8, 128.5, 128.0, 127.0, 117.4, 114.0, 113.4, 60.5, 14.3; IR (KBr)
2967, 2839, 1697, 1612, 1484, 1417, 1387, 1281, 1250, 1176 cmꢀ1; HRMS (EI) m/z: [M]+ Calcd for
C18H16N2O4 324.1110, Found 324.1108.
2,2,2ꢀTrifluoroethyl 2ꢀ(4ꢀmethoxyphenyl)imidazo[1,2ꢀa]pyridineꢀ3ꢀcarboxylate (3m‘): NMR
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yield 42%, white solid; Rf = 0.3 (EtOAc:DCM:Hexane = 1:20:20); H NMR (400 MHz, CDCl3) δ
9.39 (d, J = 0.9 Hz, J = 7.0 Hz, 1H), 8.14ꢀ8.12 (m, 2H), 7.86ꢀ7.82 (m, 3H), 7.55ꢀ7.51 (m, 1H), 7.06
(t, J = 6.9 Hz, 1H), 4.62 (q, J = 8.4 Hz, 2H), 3.96 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ
160.5, 159.2, 155.4, 148.0, 131.6, 128.9, 128.6, 126.3, 123.1 (J = 277.7 Hz), 117.7, 114.6, 113.4,
110.1, 59.9 (J = 36.9 Hz), 55.5; 19F NMR δ ꢀ73.0 ppm; IR (KBr) 2967, 2839, 1697, 1612, 1484,
1417, 1387, 1281, 1250, 1176 cmꢀ1; HRMS (EI) m/z: [M]+ Calcd for C18H13F3N2O4 378.0827,
Found 378.0831.
tertꢀButyl 2ꢀ(thiophenꢀ2ꢀyl)imidazo[1,2ꢀa]pyridineꢀ3ꢀcarboxylate (3n): yield 25.9 mg (43%),
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brown solid; mp 116−119 C; Rf = 0.3 (EtOAc:DCM:Hexane = 1:20:20); H NMR (400 MHz,
CDCl3) δ 9.32 (td, J = 1.1 Hz, 7.2 Hz, 1H), 7.93 (dd, J = 1.1 Hz, 3.7 Hz, 1H), 7.68 (d, J = 9.0 Hz,
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1H), 7.44 (dd, J = 1.1 Hz, 5.1 Hz, 1H), 7.40ꢀ7.36 (m, 1H), 7.12 (dd, J = 3.7 Hz, 5.1 Hz, 1H), 6.95
(dt, J = 1.2 Hz, 10.4 Hz, 1H), 1.63 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3) δ 160.5, 146.7, 146.4,
136.8, 129.9, 129.0, 128.6, 127.9, 127.8, 127.3, 117.4, 113.9, 82.8, 28.7; IR (KBr) 2963, 2928, 2855,
1725, 1680, 1497, 1381, 1342, 1132 cmꢀ1; HRMS (EI) m/z: [M]+ Calcd for C16H16N2O2S 300.0932,
Found 300.0930.
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2,2,2ꢀTrifluoroethyl 8ꢀmethylꢀ2ꢀphenylimidazo[1,2ꢀa]pyridineꢀ3ꢀcarboxylate (3o): yield 56.4
o
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mg (84%), white solid; mp 110−113 C; Rf = 0.3 (EtOAc:DCM:Hexane = 1:10:10); H NMR (400
MHz, CDCl3) δ 9.24 (d, J = 6.8 Hz, 1H), 7.72ꢀ7.70 (m, 2H), 7.45ꢀ7.42 (m, 3H), 7.30 (td, J = 1.0 Hz,
7.0 Hz, 1H), 7.01 (t, J = 7.0 Hz, 1H), 4.59 (q, J = 8.4 Hz, 2H), 2.70 (s, 3H); 13C{1H} NMR (100
MHz, CDCl3) δ 159.3, 155.1, 148.2, 134.4, 130.2, 129.0, 127.9, 127.8, 126.2, 123.0 (J = 266.8 Hz),
114.8, 110.9, 59.8 (J = 36.8 Hz), 17.2; 19F NMR δ ꢀ73.2 ppm; IR (KBr) 3033, 2970, 1698, 1490,
1381, 1281, 1234, 1169, 1108 cmꢀ1; HRMS (EI) m/z: [M]+ Calcd for C17H13F3N2O2 334.0929,
Found 334.0927.
Ethyl 7ꢀmethylꢀ2ꢀphenylimidazo[1,2ꢀa]pyridineꢀ3ꢀcarboxylate (3p): yield 17.4 mg (31%), white
solid; mp 48−51 oC; Rf = 0.3 (EtOAc:DCM:Hexane = 1:10:10); 1H NMR (400 MHz, CDCl3) δ 9.28
(d, J = 7.1 Hz, 1H), 7.77ꢀ7.75 (m, 2H), 7.49 (s, 1H), 7.44ꢀ7.41 (m, 3H), 6.87 (dd, J = 1.7 Hz, 7.1 Hz,
1H), 4.30 (q, J = 7.1 Hz, 2H), 2.48 (s, 3H), 1.22 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (100 MHz,
CDCl3) δ 161.3, 153.9, 147.7, 139.4, 134.8, 130.3, 130.2, 128.7, 127.8, 127.7, 116.7, 116.2, 60.5,
21.6, 14.1; IR (KBr) 3058, 2979, 2929, 1684, 1400, 1225, 1155, 1050 cmꢀ1; HRMS (EI) m/z: [M]+
Calcd for C17H16N2O2 280.1212, Found 280.1213.
2,2,2ꢀTrifluoroethyl 7ꢀmethylꢀ2ꢀphenylimidazo[1,2ꢀa]pyridineꢀ3ꢀcarboxylate (3p´): yield 33.5
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mg (50%), white solid; mp 108−111 C; Rf = 0.2 (EtOAc:DCM:Hexane = 1:10:10); H NMR (400
MHz, CDCl3) δ 9.24 (d, J = 7.1 Hz, 1H), 7.73ꢀ7.71 (m, 2H), 7.53 (s, 1H), 7.45ꢀ7.43 (m, 3H), 6.94
(dd, J = 1.7 Hz, 7.1 Hz, 1H), 4.60 (q, J = 8.5 Hz, 2H), 2.50 (s, 3H); 13C{1H} NMR (100 MHz,
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CDCl3) δ 159.2, 155.7, 148.4, 140.5, 134.1, 130.1, 129.1, 127.9, 127.7, 123.1 (J = 277.7 Hz), 117.3,
116.5, 110.1, 59.8 (J = 36.9 Hz), 21.6; 19F NMR δ ꢀ73.1 ppm; IR (KBr) 3036, 2969, 2925, 1693,
1413, 1281, 1169, 1069 cmꢀ1; HRMS (EI) m/z: [M]+ Calcd for C17H13F3N2O2 334.0929, Found
334.0926.
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Ethyl 7ꢀethylꢀ2ꢀphenylimidazo[1,2ꢀa]pyridineꢀ3ꢀcarboxylate (3q, minor): NMR yield 15%,
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white solid; Rf = 0.4 (EtOAc:DCM:Hexane = 1:20:20); H NMR (400 MHz, CDCl3) δ 9.30 (d, J =
7.2 Hz, 1H), 7.78ꢀ7.75 (m, 2H), 7.52 (s, 1H), 7.44ꢀ7.42 (m, 3H), 6.91 (d, J = 6.8 Hz, 1H), 4.30 (q, J
= 7.1 Hz, 2H), 2.76 (q, J = 8.0 Hz, 2H), 1.22 (t, J = 7.1 Hz, 3H), 1.22 (t, J = 7.1 Hz, 3H); IR (KBr)
3138, 3062, 2971, 2931, 1692, 1406, 1283, 1163 cmꢀ1; HRMS (EI) m/z: [M]+ Calcd for C18H18N2O2
294.1368, Found 294.1368.
2,2,2ꢀTrifluoroethyl 7ꢀethylꢀ2ꢀphenylimidazo[1,2ꢀa]pyridineꢀ3ꢀcarboxylate (3q‘, major): NMR
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yield 59%, white solid; Rf = 0.4 (EtOAc:DCM:Hexane = 1:20:20); H NMR (400 MHz, CDCl3) δ
9.25 (d, J = 7.1 Hz, 1H), 7.74ꢀ7.71 (m, 2H), 7.56 (s, 1H), 7.44ꢀ7.42 (m, 3H), 6.97 (d, J = 7.1 Hz,
1H), 4.60 (q, J = 8.5 Hz, 2H), 2.80 (q, J = 7.6 Hz, 2H), 1.33 (t, J = 7.6 Hz, 3H); 13C{1H} NMR (100
MHz, CDCl3) δ 159.2, 155.8, 148.6, 146. 5, 134.2, 130.3, 130.1, 129.0, 127.9, 127.7, 120.1 (J =
295.8 Hz), 116.3, 115.1, 59.8 (J = 37.0 Hz), 28.6, 14.4; 19F NMR δ ꢀ73.1 ppm; IR (KBr) 3138, 3062,
2971, 2931, 1692, 1406, 1283, 1163 cmꢀ1; HRMS (EI) m/z: [M]+ Calcd for C18H15F3N2O2 348.1086,
Found 348.1085.
Ethyl 8ꢀbromoꢀ2ꢀphenylimidazo[1,2ꢀa]pyridineꢀ3ꢀcarboxylate (3r): yield 53.9 mg (78%), white
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solid; mp 109ꢀ110 C; Rf = 0.5 (EtOAc:DCM:Hexane = 1:20:20); H NMR (400 MHz, CDCl3) δ
9.43 (dd, J = 1.0 Hz, 7.0 Hz, 1H), 7.77ꢀ7.75 (m, 2H), 7.69 (dd, J = 1.0 Hz, 7.4 Hz, 1H), 7.44ꢀ7.42
(m, 3H), 6.92 (t, J = 7.2 Hz, 1H), 4.30 (q, J = 7.1 Hz, 2H), 1.20 (t, J = 7.1 Hz, 3H); 13C{1H} NMR
(100 MHz, CDCl3) δ 161.2, 154.0, 145.1, 134.2, 130.5, 130.4, 128.9, 127.7, 114.2, 113.8, 111.7,
60.9, 14.0; IR (KBr) 2980, 1685, 1490, 1402, 1322, 1239, 1156 cmꢀ1; HRMS (EI) m/z: [M]+ Calcd
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for C16H1379BrN2O2 344.0160, C16H1381BrN2O2 346.0142, Found 344.0158, 346.0140.
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solid; mp 109ꢀ110 C; Rf = 0.5 (EtOAc:DCM:Hexane = 1:20:20); H NMR (400 MHz, CDCl3) δ
9.43 (dd, J = 1.0 Hz, 6.9 Hz, 1H), 7.92 (dd, J = 1.0 Hz, 7.3 Hz, 1H), 7.78ꢀ7.76 (m, 2H), 7.44ꢀ7.41
(m, 3H), 6.78 (t, J = 7.1 Hz, 1H), 4.29 (q, J = 7.1 Hz, 2H), 1.20 (t, J = 7.1 Hz, 3H); 13C{1H} NMR
(100 MHz, CDCl3) δ 161.4, 153.8, 146.4, 137.2, 134.3, 130.6, 128.9, 128.5, 127.7, 114.8, 113.9,
84.0, 60.8, 14.0; IR (KBr) 2979, 1685, 1488, 1400, 1320, 1238, 1202, 1163, 1054 cmꢀ1; HRMS (EI)
m/z: [M]+ Calcd for C16H13N2O2I 392.0022, Found 392.0019.
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Ethyl 7ꢀacetylꢀ2ꢀphenylimidazo[1,2ꢀa]pyridineꢀ3ꢀcarboxylate (3t): yield 58.6 mg (95%), white
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solid, mp 148ꢀ150 C; Rf = 0.4 (EtOAc:DCM:Hexane = 1:20:20); H NMR (400 MHz, CDCl3)
δ
9.43 (d, J = 0.8 Hz, 7.3 Hz, 1H), 8.29 (q, J = 0.8 Hz, 1H), 7.79ꢀ7.77 (m, 2H), 7.60 (dd, J = 1.8 Hz,
7.3 Hz, 1H), 7.47ꢀ7.45 (m, 3H), 4.34 (q, J = 7.1 Hz, 2H), 2.70 (s, 3H), 1.25 (t, J = 7.1 Hz, 3H);
13C{1H} NMR (100 MHz, CDCl3)
δ 195.8, 161.0, 155.0, 146.2, 135.4, 134.0, 130.3, 129.2, 128.3,
127.8, 119.0, 113.6, 111.7, 61.0, 26.4, 14.1; IR (KBr) 3057, 2988, 2926, 1684, 1403, 1381, 1312,
1231 cmꢀ1; HRMS (EI) m/z: [M]+ Calcd for C18H16N2O3 308.1161, Found 308.1162.
3ꢀEthyl 7ꢀmethyl 2ꢀphenylimidazo[1,2ꢀa]pyridineꢀ3,7ꢀdicarboxylate (3u): yield 44.1 mg (68%),
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white solid, mp 123ꢀ125 C; Rf = 0.2 (EtOAc:DCM:Hexane = 1:10:10); H NMR (400 MHz,
CDCl3)
δ 9.45 (d, J = 7.3 Hz, 1H), 8.42 (s, 1H), 7.78ꢀ7.76 (m, 2H), 7.62 (dd, J = 1.7 Hz, 7.3 Hz,
1H), 7.47ꢀ7.43 (m, 3H), 4.33 (q, J = 7.1 Hz, 2H), 4.00 (s, 3H), 1.24 (t, J = 7.1 Hz, 3H); 13C{1H}
NMR (100 MHz, CDCl3)
δ 165.3, 161.0, 155.0, 146.2, 134.1, 130.3, 129.2, 129.1, 128.1, 127.8,
119.8, 113.4, 113.3, 61.0, 52.9, 14.1; IR (KBr) 3136, 3068, 2983, 2953, 1725, 1688, 1489, 1406,
1324 cmꢀ1; HRMS (EI) m/z: [M]+ Calcd for C18H16N2O4 324.1110, Found 324.1107.
Ethyl 2ꢀphenylimidazo[1,2ꢀa]quinolineꢀ1ꢀcarboxylate (3v): yield 53.8 mg (85%), white solid; mp
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89−91 C; Rf = 0.4 (EtOAc:DCM:Hexane = 1:10:10); H NMR (400 MHz, CDCl3) δ 8.12 (d, J =
8.7 Hz, 1H), 7.85ꢀ7.81 (m, 3H), 7.70 (d, J = 9.3 Hz, 1H), 7.65ꢀ7.61 (m, 2H), 7.52ꢀ7.40 (m, 4H),
4.38 (q, J = 7.1 Hz, 2H), 1.21 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 163.1, 150.9,
146.0, 134.0, 133.5, 129.8, 129.7, 129.4, 128.8, 128.7, 128.1, 125.4, 124.6, 118.3, 117.0, 116.2, 61.9,
14.0; IR (KBr) 3058, 2979, 1710, 1445, 1370, 1193 cmꢀ1; HRMS (EI) m/z: [M]+ Calcd for
C20H16N2O2 316.1212, Found 316.1209.
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Ethyl 2ꢀphenylimidazo[2,1ꢀa]isoquinolineꢀ3ꢀcarboxylate (3w): yield 51.3 mg (81%), white solid;
mp 125−127 oC; Rf = 0.3 (EtOAc:DCM:Hexane = 1:20:20); 1H NMR (400 MHz, CDCl3) δ 9.17 (d,
J = 7.5 Hz, 1H), 8.80 (q, J = 3.1 Hz, 1H), 7.82ꢀ7.79 (m, 3H), 7.69ꢀ7.67 (m, 2H), 7.48–7.42 (m, 3H),
7.27 (d, J = 8.7 Hz, 1H), 4.33 (q, J = 7.1 Hz, 2H), 1.24 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (100
MHz, CDCl3) δ 161.4, 152.0, 145.2, 134.8, 130.6, 130.4, 129.6, 128.6, 128.4, 127.8, 126.8, 124.6,
124.5, 123.2, 114.3, 113.8, 60.7, 14.1; IR (KBr) 3134 ,3056, 2979, 2904, 1692, 1516, 1400, 1369,
1222, 1163 cmꢀ1; HRMS (EI) m/z: [M]+ Calcd for C20H16N2O2 316.1212, Found 316.1209.
Ethyl 2,7ꢀdiphenylimidazo[1,2ꢀa]pyridineꢀ3ꢀcarboxylate (3x): yield 15.1 mg (22%), white solid;
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mp 168−170 C; Rf = 0.35 (EtOAc:DCM:Hexane = 1:20:20); H NMR (400 MHz, CDCl3) δ 9.44
(dd, J = 0.9 Hz, 7.3 Hz, 1H), 7.94 (q, J = 0.9 Hz, 1H), 7.81ꢀ7.79 (m, 2H), 7.72ꢀ7.70 (m, 2H), 7.53ꢀ
7.49 (m, 2H), 7.47ꢀ7.42 (m, 4H), 7.33 (dd, J = 1.9 Hz, 7.3 Hz 1H), 4.33 (q, J = 8.4 Hz, 2H) 1.24 (t,
J = 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 161.2, 154.4, 147.8, 141.0, 138.1, 134.6,
130.3, 129.4, 129.0, 128.8, 128.3, 127.7, 127.1, 114.2, 113.8, 111.9, 60.6, 14.1; IR (KBr) 3033,
2985, 2904, 1671, 1406, 1381, 1227, 1165, 1049 cmꢀ1; HRMS (EI) m/z: [M]+ Calcd for C22H18N2O2
342.1368, Found 342.1370.
2,2,2ꢀTrifluoroethyl 2,7ꢀdiphenylimidazo[1,2ꢀa]pyridineꢀ3ꢀcarboxylate (3x´): yield 30.9 mg
(39%), white solid; mp 195−197 oC; Rf = 0.4 (EtOAc:DCM:Hexane = 1:20:20); 1H NMR (400 MHz,
CDCl3) δ 9.40 (dd, J = 0.7 Hz, 7.3 Hz, 1H), 7.98 (q, J = 0.9 Hz, 1H), 7.77ꢀ7.75 (m, 2H), 7.73ꢀ7.70
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(m, 2H), 7.55ꢀ7.51 (m, 2H), 7.48ꢀ7.45 (m, 4H), 7.39 (dd, J = 1.9 Hz, J = 7.3 Hz, 1H), 4.63 (q, J =
8.4 Hz, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 159.1, 156.2, 148.5, 141.9, 137.8, 134.0, 130.1,
129.4, 129.2, 129.1, 128.4, 127.9, 127.1, 123.1 (J = 277.6 Hz), 114.4, 114.3, 110.3, 59.9 (J = 36.9
Hz); 19F NMR δ ꢀ73.1 ppm; IR (KBr) 3033, 2985, 2904, 1671, 1406, 1381, 1227, 1165, 1049 cmꢀ1;
HRMS (EI) m/z: [M]+ Calcd for C22H15F3N2O2 396.1086, Found 396.1088.
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Ethyl 2ꢀphenylꢀ7ꢀ(pꢀtolyl)imidazo[1,2ꢀa]pyridineꢀ3ꢀcarboxylate (3y): yield 14.3 mg (20%),
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white solid; mp 176−178 C; Rf = 0.25 (EtOAc:DCM:Hexane = 1:20:20); H NMR (400 MHz,
CDCl3) δ 9.42 (dd, J = 0.6 Hz, 7.3 Hz, 1H), 7.92 (q, J = 0.9 Hz, 1H), 7.81ꢀ7.78 (m, 2H) 7.61 (d, J =
8.2 Hz, 2H), 7.45ꢀ7.42 (m, 3H), 7.33ꢀ7.30 (m, 3H), 4.32 (q, J = 7.1 Hz, 2H), 2.43 (s, 3H), 1.24 (t, J
= 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 161.3, 154.4, 147.9, 141.0, 139.1, 135.2, 134.7,
130.3, 130.1, 128.8, 128.3, 127.7, 126.9, 113.8, 111.8, 60.6, 29.8, 21.4, 14.2; IR (KBr) 2988, 2921,
1674, 1382, 1226, 1163, 1050 cmꢀ1; HRMS (EI) m/z: [M]+ Calcd for C23H20N2O2 356.1525, Found
356.1522.
2,2,2ꢀTrifluoroethyl 2ꢀphenylꢀ7ꢀ(pꢀtolyl)imidazo[1,2ꢀa]pyridineꢀ3ꢀcarboxylate (3y´): yield 32.0
o
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mg (39%), white solid; mp 191−193 C; Rf = 0.3 (EtOAc:DCM:Hexane = 1:20:20); H NMR (400
MHz, CDCl3) δ 9.37 (d, J = 7.3 Hz, 1H), 7.95 (s, 1H), 7.77ꢀ7.74 (m, 2H), 7.61 (d, J = 8.2 Hz, 2H),
7.47ꢀ7.44 (m, 3H), 7.37 (dd, J = 1.9 Hz, 7.3 Hz, 1H), 7.33 (q, J = 8.0 Hz, 2H), 4.62 (q, J = 8.5 Hz,
2H), 2.43 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 159.1, 156.2, 148.6, 141.9, 139.4, 134.9,
134.1, 130.1, 129.2, 128.3, 127.9, 127.2, 126.9, 123.1 (J = 277.7 Hz), 114.3, 113.9, 110.2, 59.9 (J =
36.9 Hz), 21.4, 1.2; 19F NMR δ ꢀ73.1 ppm; IR (KBr) 2960, 2351, 1675, 1385, 1286, 1176, 1156,
1067 cmꢀ1; HRMS (EI) m/z: [M]+ Calcd for C23H17F3N2O2 410.1242, Found 410.1242.
Ethyl 7ꢀ(4ꢀchlorophenyl)ꢀ2ꢀphenylimidazo[1,2ꢀa]pyridineꢀ3ꢀcarboxylate (3z): yield 24.9 mg
o
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(33%), white solid; mp 213−215 C; Rf = 0.25 (EtOAc:DCM:Hexane = 1:20:20); H NMR (400
MHz, CDCl3) δ 9.45 (dd, J = 0.8 Hz, 7.3 Hz, 1H), 7.90 (q, J = 0.9 Hz, 1H) 7.80ꢀ7.78 (m, 2H), 7.63
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(dd, J = 1.9 Hz, 6.6 Hz, 2H) 7.50ꢀ7.43 (m, 5H), 7.28ꢀ7.26 (m, 1H), 4.33 (q, J = 7.1 Hz, 2H), 1.24 (t,
J = 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 161.2, 154.5, 147.6, 139.6, 136.6, 135.2,
134.5, 130.3, 129.6, 128.9, 128.5, 128.3, 127.7, 114.2, 113.5, 112.0, 60.7, 14.1; IR (KBr) 3028,
2966, 2925, 2349, 1668, 1488, 1226, 1168 cmꢀ1; HRMS (EI) m/z: [M]+ Calcd for C22H17ClN2O2
376.0979, Found 376.0981.
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2,2,2ꢀTrifluoroethyl 7ꢀ(4ꢀchlorophenyl)ꢀ2ꢀphenylimidazo[1,2ꢀa]pyridineꢀ3ꢀcarboxylate (3z´):
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yield 34.5 mg (40%), white solid; mp 199−201 C; Rf = 0.3 (EtOAc:DCM:Hexane = 1:20:20); H
NMR (400 MHz, CDCl3) δ 9.40 (d, J = 7.2 Hz, 1H), 7.93 (s, 1H), 7.75 (q, J = 3.2 Hz, 2H), 7.64 (d,
J = 8.5 Hz, 2H), 7.50ꢀ7.45 (m, 5H), 7.33 (dd, J = 1.8 Hz, 7.3 Hz, 1H), 4.63 (q, J = 8.4 Hz, 2H);
13C{1H} NMR (100 MHz, CDCl3) δ 159.1, 156.3, 148.3, 140.6, 136.3, 135.5, 133.9, 130.1, 129.7,
129.3, 128.6, 128.3, 128.0, 123.0 (J = 278.0 Hz), 114.4, 114.0, 110.4, 60.0 (J = 36.9 Hz); 19F NMR
δ ꢀ73.1 ppm; IR (KBr) 2964, 2920, 1670, 1387, 1290, 1224, 1166, 1068 cmꢀ1; HRMS (EI) m/z: [M]+
Calcd for C22H14ClF3N2O2 430.0696, Found 430.0694.
Ethyl 8ꢀmethoxyꢀ2ꢀphenylꢀ7,8ꢀdihydroimidazo[1,2ꢀa]pyridineꢀ3ꢀcarboxylate (4a): yield 14.9
o
mg (25%), white solid; mp 70−72 C; Rf = 0.1 (EtOAc:Hexane = 1:5); 1H NMR (400 MHz, CDCl3)
δ 7.77ꢀ7.74 (m, 1H), 7.69ꢀ7.67 (m, 2H), 7.43ꢀ7.36 (m, 3H), 5.69ꢀ5.65 (m, 1H), 4.52 (ddd, J = 0.8
Hz, 2.4 Hz, 5.3 Hz, 1H), 4.26 (q, J = 7.1 Hz, 2H), 3.42 (s, 3H), 2.81ꢀ2.64 (m, 2H), 1.21(t, J = 7.1
Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 160.9, 148.0, 144.7, 134.1, 129.8, 128.3, 127.7, 123.5,
116.9, 112.0, 70.1, 60.9, 57.1, 28.2, 14.0; IR (KBr) 2981, 2928, 2824, 1701, 1437, 1373, 1226, 1146,
1087 cmꢀ1; HRMS (EI) m/z: [M]+ Calcd for C17H18N2O3 298.1317, Found 298.1317.
Ethyl 2ꢀphenylimidazo[1,2ꢀb]pyridazineꢀ3ꢀcarboxylate (6a): yield 42.9 mg (80%), white solid;
mp 89−91 oC; Rf = 0.2 (EtOAc:DCM:Hexane = 1:3:3); 1H NMR (400 MHz, CDCl3) δ 8.57 (dd, J =
1.6 Hz, 4.4 Hz, 1H), 8.05 (dd, J = 1.6 Hz, 9.2 Hz, 1H), 7.82ꢀ7.80 (m, 2H), 7.49ꢀ7.43 (m, 3H), 7.24
13
(q, J = 4.5 Hz, 1H ), 4.40 (q, J = 7.1 Hz, 2H), 1.27 (t, J = 7.1 Hz, 3H); C{1H} NMR (100 MHz,
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CDCl3) δ 159.9, 151.2, 144.0, 140.7, 133.8, 129.8, 129.1, 128.0, 125.7, 119.4, 116.9, 61.2, 14.1; IR
(KBr) 2980, 2917, 1714, 1531, 1485, 1415, 1329, 1279, 1183 cmꢀ1; HRMS (EI) m/z: [M]+ Calcd for
C15H13N3O2 267.1008, Found 267.1009.
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Ethyl 6ꢀmethylꢀ2ꢀphenylimidazo[1,2ꢀb]pyridazineꢀ3ꢀcarboxylate (6b): yield 54.0 mg (96%),
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white solid; mp 107−109 C; Rf = 0.3 (EtOAc:DCM:Hexane = 1:3:3); 1H NMR (400 MHz, CDCl3)
δ 7.91 (d, J = 9.2 Hz, 1H), 7.80ꢀ7.78 (m, 2H), 7.46ꢀ7.42 (m, 3H), 7.10 (d, J = 9.3 Hz, 1H), 4.38 (q, J
= 7.1 Hz, 2H), 2.69 (s, 3H), 1.27 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 160.1,
153.2, 150.6, 139.8, 134.0, 129.8, 128.9, 128.0, 125.2, 121.5, 116.8, 61.1, 22.3, 14.1; IR (KBr) 2981,
1715, 1616, 1547, 1338 cmꢀ1; HRMS (EI) m/z: [M]+ Calcd for C16H15N3O2 281.1164, Found
281.1161.
Ethyl 7ꢀmethylꢀ2ꢀphenylimidazo[1,2ꢀc]pyrimidineꢀ3ꢀcarboxylate (6c): yield 30.4 mg (54%),
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white solid; mp 73−76 C; Rf = 0.3 (EtOAc:DCM:Hexane = 1:3:3); H NMR (400 MHz, CDCl3) δ
10.05 (d, J = 1.1 Hz, 1H), 7.81ꢀ7.78 (m, 2H), 7.46ꢀ7.42 (m, 4H), 4.35 (q, J = 7.1 Hz, 2H), 2.62 (d, J
= 0.4 Hz, 3H), 1.27 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 160.6, 154.8, 152.9,
147.9, 140.4, 133.5, 130.4, 129.4, 127.8, 110.8, 109.9, 61.1, 23.9, 14.1; IR (KBr) 2980, 1758, 1685,
1580, 1334 cmꢀ1; HRMS (EI) m/z: [M]+ Calcd for C16H15N3O2 281.1164, Found 281.1166.
Ethyl 2ꢀphenylimidazo[1,2ꢀa]pyrazineꢀ3ꢀcarboxylate (6d): yield 28.4 mg (53%), white solid; mp
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89−91 C; Rf = 0.3 (EtOAc:Hexane = 1:2); H NMR (400 MHz, CDCl3) δ 9.25ꢀ9.23 (m, 2H), 8.15
(d, J = 4.6 Hz, 1H), 7.81ꢀ7.78 (m, 2H), 7.47ꢀ7.46 (m, 3H), 4.37 (q, J = 7.1 Hz, 2H), 1.27 (t, J = 7.1
Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 160.7, 154.1, 143.9, 141.5, 133.5, 131.8, 130.4, 129.4,
127.9, 120.7, 113.2, 61.3, 14.1; IR (KBr) 3138, 3065, 2992, 1685, 1487, 1474, 1402, 1383, 1254,
1209, 1164 cmꢀ1; HRMS (EI) m/z: [M]+ Calcd for C15H13N3O2 267.1008, Found 267.1006.
Ethyl 8ꢀmethylꢀ2ꢀphenylimidazo[1,2ꢀa]pyrazineꢀ3ꢀcarboxylate (6e): yield 33.1 mg (59%), white
solid; mp 130−132 oC; Rf = 0.3 (EtOAc:DCM:Hexane = 1:3:3); 1H NMR (400 MHz, CDCl3) δ 9.10
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(d, J = 4.7 Hz, 1H), 8.00 (d, J = 4.7 Hz, 1H), 7.78ꢀ7.76 (m, 2H), 7.47ꢀ7.44 (m, 3H), 4.34 (q, J = 7.1
Hz, 2H), 2.97 (s, 3H) 1.24 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 160.8, 153.3,
153.2, 141.2, 133.9, 131.1, 130.4, 129.2, 127.9, 119.1, 113.6, 61.2, 20.9, 14.1; IR (KBr) 2997, 2983,
1684, 1481, 1409, 1257, 1168 cmꢀ1; HRMS (EI) m/z: [M]+ Calcd for C16H15N3O2 281.1164, Found
281.1163.
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Ethyl 6,8ꢀdimethylꢀ2ꢀphenylimidazo[1,2ꢀa]pyrazineꢀ3ꢀcarboxylate (6f): yield 41.9 mg (71%),
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yllow solid; mp 128−130 C; Rf = 0.2 (EtOAc:DCM:Hexane = 1:5:5); 1H NMR (400 MHz, CDCl3)
δ 8.96 (s, 1H), 7.76ꢀ7.74 (m, 2H), 7.46ꢀ7.43 (m, 3H), 4.32 (q, J = 7.1 Hz, 2H), 2.95 (s, 3H), 2.58 (s,
3H), 1.23 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 161.0, 153.3, 151.9, 140.1, 134.2,
130.3 (2C), 129.0, 127.8 (2C), 116.2, 61.0, 21.4, 20.8, 14.1; IR (KBr) 2981, 2925, 1690, 1488, 1406,
1379, 1290, 1171, 1132 cmꢀ1; HRMS (EI) m/z: [M]+ Calcd for C17H17N3O2 295.1321, Found
295.1324.
General Procedure for the C–H Activations
2,2,2ꢀTrifluoroethyl
2ꢀ(2ꢀ((4ꢀmethylphenyl)sulfonamido)phenyl)imidazo[1,2ꢀa]pyridineꢀ3ꢀ
carboxylate (7): To an ovenꢀdried test tube equipped with a stirring bar, 3a´ (64.1 mg, 0.2 mmol),
tosyl azide (47.3 mg, 0.24 mmol), [Cp*IrCl2]2 (4.0 mol %), AgPF6 (16.0 mol %), and
dichloroethane (1.0 mL) were added and then pivalic acid (11.0 ꢀL, 0.1 mmol) was added. The
o
resulting mixture was stirred at 80 C for 10 h. After celite filtration with dichloromehane and
evaporation of the solvents in vacuo, the residue was purified by Silica gel flash column
chromatography (EtOAc:Hexane = 1:2) to give 7 (76.4 mg, 78%). white solid; mp 178−180 oC; Rf =
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0.2 (EtOAc:Hexane = 1:2); H NMR (400 MHz, CDCl3) δ 9.32ꢀ9.30 (m, 2H), 7.79 (d, J = 8.9 Hz,
1H), 7.70 (d, J = 8.0 Hz, 1H), 7.64ꢀ7.59 (m, 1H), 7.47ꢀ7.42 (m, 2H), 7.24ꢀ7.16 (m, 2H), 7.07 (d, J =
8.2 Hz, 2H), 6.64 (d, J = 8.0 Hz, 2H), 4.44 (q, J = 8.4 Hz, 2H), 2.21 (s, 3H); 13C{1H} NMR (100
MHz, CDCl3) δ 158.1, 151.4, 147.1, 143.0, 136.5, 135.1, 132.3, 130.5, 129.7, 128.6, 128.3, 127.0,
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