Copper(II)-Mediated Aerobic Synthesis of Imidazo[1,2-a]pyridines via Cascade Aminomethylation/Cycloisomerization of Alkynes

Article abstract of DOI:10.1021/acs.joc.5b02102

A single copper(II)-catalyzed three-component cascade aminomethylation/cycloisomerization of propiolates to form imidazo[1,2-a]pyridines was explored. A straightforward method was developed for the practical synthesis of functionalized imidazo[1,2-a]pyridines from benzaldehydes, 2-aminopyridines, and propiolate derivatives catalyzed by Cu(OAc)₂ hydrate in the presence of air. The protocol is marked by excellent yields, functional group tolerance, and, above all, adaptability to synthesize imidazo[1,2-a]pyridine-based drug molecules such as Alpidem.

Full text of DOI:10.1021/acs.joc.5b02102

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Note
Copper(II)-Mediated Aerobic Synthesis of Imidazo[1,2-a]pyridines
via Cascade Aminomethylation/Cycloisomerization of Alkynes
Irina V. Rassokhina, Valerii Z. Shirinian, Igor V. Zavarzin, Vladimir Gevorgyan, and Yulia Alexeevna Volkova
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b02102 • Publication Date (Web): 12 Oct 2015
Downloaded from http://pubs.acs.org on October 15, 2015
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Copper(II)-Mediated Aerobic Synthesis of Imidazo[1,2-a]pyridines via Cascade
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Aminomethylation/Cycloisomerization of Alkynes
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Irina V. Rassokhina,† Valerii Z. Shirinian,† Igor V. Zavarzin,† Vladimir Gevorgyan‡ and Yulia A.
Volkova†*
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†
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 47 Leninsky prosp.,
119991 Moscow (Russia).
Tel.: +7 (499) 136 89 60, eꢀmail: yavolkova@gmail.com
‡
Department of Chemistry, University of Illinois at Chicago, 845 West Taylor Street, Room 4500,
Chicago, IL 60607 (USA).
Abstract:
A single copper(II)ꢀcatalyzed threeꢀcomponent cascade aminomethylation/cycloisomerization of
propiolates to form imidazo[1,2ꢀa]pyridines was explored. A straightforward method was developed
for the practical synthesis of functionalized imidazo[1,2ꢀa]pyridines from benzaldehydes, 2ꢀ
aminopyridines and propiolate derivatives catalyzed by Cu(OAc)2 hydrate in the presence of air. The
protocol is marked by excellent yields, functional group tolerance and, above all, adaptability to
synthesize imidazo[1,2ꢀa]pyridineꢀbased drug molecules such as Alpidem.
Keywords: imidazo[1,2ꢀa]pyridines; copper catalysis; alkynes; cascade reaction.
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Imidazo[1,2ꢀa]pyridines are challenging templates in the context of CNS therapies.1 Many drugs
with imidazo[1,2ꢀa]pyridine scaffold (zolpidem, alpidem, zolimidine, olprinone, saripidem and
necopidem) are extensively prescribed as sedatives, anxiolytics, anticonvulsants, or muscle relaxants.2
Moreover, the continuous appearance of reports describing novel pharmacological activities of these
compounds, e.g., inhibition of farnesyl pyrophosphate synthase (minodronic acid), antimalarial
agents,3 bromodomain4 and c Met tyrosine kinase inhibitors5 for cancer treatment,etc.,6
unequivocally corroborate the ability of imidazopyridines to modulate relevant biomolecules beyond
CNS targets (figure 1).
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The prevalence of the imidazopyridine scaffold in medically relevant compounds,6 dyes,7 ligands
for metal catalysts8 and materials9 has inspired the development of many novel methods for their
preparation.10 However, there are only limited protocols for assembling 3ꢀmethylenecarbonylꢀ
substituted imidazo[1,2ꢀa]pyridine derivatives, important pharmacophores11 and promising
intermediates in organic synthesis.12 Traditional methods include the heterocyclization of 2ꢀ
aminopyridines with bromo keto esters13 and α,βꢀunsaturated carbonyl compounds.14 Alternatively,
the double azaꢀMichael addition reaction of Morita−Baylis−Hillman acetates of nitroalkenes with 2ꢀ
aminopyridines15 was described. Despite that, it is still a great challenge to synthesize functionalized
imidazopyridines from readily available and easily varied starting materials using a simple procedure.
Figure 1. Imidazo[1,2ꢀa]pyridineꢀbased drug molecules.
Recently, some of us16 developed a new threeꢀcomponent copperꢀcatalyzed reaction for the
synthesis of imidazo[1,2ꢀa]pyridines from conveniently available 2ꢀaminopyridines, aldehydes and
terminal alkynes (Scheme 1). This reaction is believed to undergo three cascade processes namely (1)
Schiffꢀbase formation from amine and aldehyde, (2) copperꢀmediated electrophilic aminomethylation
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of alkyne with the Schiffꢀbase leading to propargylamine, (3) final 5-exo-dig nucleophilic cyclization
giving imidazo[1,2ꢀa]pyridine. Initially, a mixed Cu(I)/Cu(II) catalysis under inert atmosphere was
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used to obtain high product yields. To date several modifications of copper(I) catalysts such as
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CuHal/Cu(OTf)2,17 CuSO4
•
5H2O/Dꢀglucose,18 CuCl/ZnCl2 and CuI/NaHSO4/SiO220 were proposed
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for this process. However, reactants are generally limited to aryl(alkyl)acetylenes, while procedures
suffer from stringent anaerobic and harsh conditions. Attempts to use a single copper(II) catalysts in
this reaction were incompetent.21 Only the CuHalꢀCu(OTf)2 pair was shown to be suitable for
heterocyclization of propiolate derivatives providing direct access to the 3ꢀmethylenecarbonylꢀ
substituted imidazo[1,2ꢀa]pyridine scaffold of drugs (Scheme 1).16,17 Cascade copper(II)ꢀpromoted
heterocyclization of propiolates with imines is, to the best of our knowledge, unknown to date.
Scheme 1. Synthesis of imidazo[1,2ꢀa]pyridines via the copperꢀcatalyzed cascade threeꢀcomponent
reaction of 2ꢀaminopyridines, benzaldehydes and terminal alkynes
Meanwhile, the aerobic copper(II) catalysis22 was found to be highly effective in the synthesis of
diverse Nꢀheterocycles,23 including imidazopyridines.24 Namely, the CuCl2ꢀcatalyzed oxidative
heterocyclization of functionalized Schiffꢀbases to form imidazo[1,5ꢀa]pyridines was described.24a
The elegant synthesis of imidazo[1,2ꢀa]pyridineꢀ3ꢀcarbaldehydes via [Cu(hfacac)2·xH2O]ꢀcatalyzed
dehydrogenative aminooxygenation of allylꢀ2ꢀaminoꢀ5ꢀmethylpyrines was reported.24b These
processes are valued for their mild reaction conditions and functional group tolerance.
Taking into account that Larsen and coꢀworkers showed that aminomethylation of acetylenes with
imines (the second step of the aboveꢀmentioned cascade reaction) can be successfully performed
exclusively under Cu(OTf)2 catalysis,25 we were prompted to develop a practical efficient approach to
imidazo[1,2ꢀa]pyridines promoted with a copper(II)ꢀoxygen catalytic system. Research was focused
on propiolate derivatives as the most challenging starting materials.
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In this regard, we commenced the optimization studies with ethyl propiolate (1a) and imine (2a), as
model substrates, using a series of different copper sources under air (Table 1). Among the copper
salts screened, Cu(OTf)2 and Cu(acac)2 showed promising results by providing the desired product 3a
in good yields, 69% and 72%, respectively (Table 1, entries 5 and 6). A comparison of the efficiency
of Cu(II) and Cu(I) showed the superior activity of Cu(II) (Table 1, entries 1ꢀ3, 5 and 6). The only
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exception was CuOTf•C6H6, which produced a comparable yield (67%, Table 1, entry 4). The best
results were achieved by performing the reaction with Cu(OAc)2 hydrate in toluene at 120 oC to afford
compound 3a in 95% isolated yield (Table 1, entry 7). The reactions in different solvents, including
DCE and acetonitrile, gave low yields of product 3a (11%, Table 1, entries 10 and 11), whereas neat
conditions, DCM and water were ineffective and led to traces of the product (Table 1, entries 8,9 and
12). Besides the reaction of 1 equiv of 1a with imine 2a in the presence of Cu(OAc)2 hydrate afforded
3a in yield of 39% (Table 1, entry 13) versus 95% when using 2 equiv of 1a.
Table 1. Optimization of the reaction conditionsa
yield
3a,%
entry
catalyst
solvent
T, oC
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CuBr
СuCl
toluene
toluene
toluene
toluene
toluene
toluene
toluene
neat
CH2Cl2
C2H4Cl2
CH3CN
H2O
120
120
120
120
120
120
120
100
54
100
100
120
120
25b
24c
59b
67b
69c
72c
95c
5b
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CuSO4 5H2O
CuOTf•C6H6
Cu(OTf)2
Cu(acac)2
Cu(OAc)2•H2O
Cu(OAc)2•H2O
Cu(OAc)2•H2O
Cu(OAc)2•H2O
Cu(OAc)2•H2O
Cu(OAc)2•H2O
Cu(OAc)2•H2O
5b
11b
11b
ꢀ
toluene
39d,e
a)Reaction conditions: imine 2a (0.20 mmol), ethyl
propiolate 1a (2 equiv), Cu salt (10 mol %), solvent (1
mL) in a screwꢀcapped vial under air.b) Determined
1
с)
by H NMR. Isolated yield.d) Reaction with 1 equiv
e)
of ethyl propiolate 1a.
conversion of 2a.
Yield with respect of 85%
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Based on the above results, then we developed a oneꢀpot threeꢀcomponent protocol using the
following standard reaction conditions: 10 mol % of Cu(OAc)2 hydrate, 1.0 equiv. of amine, 1.1 equiv.
o
of aldehyde and 2.0 equiv. of propiolate in toluene at 120 C in a screwꢀcapped vial under air in the
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presence of molecular sieves. Ethyl propiolate and copper catalysts were added to the reaction mixture
upon completion of the dehydrocondensation step. The yield of 3a under oneꢀpot conditions was still
quantitative (95% after column chromatography).
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Having the optimal conditions in hand, we investigated the scope of the oneꢀpot threeꢀcomponent
protocol for the reaction of a series of substituted aryl aldehydes 4 and 2ꢀaminopyridines 5 with ethyl
propiolate 1a as a representative example (Table 2).
Aryl aldehydes containing electronꢀdonating and ꢀwithdrawing groups were exposed to the reaction
with unsubstituted 2ꢀaminopyridine. The electronꢀwithdrawing substituents in ortoꢀ, metaꢀ and paraꢀ
positions such as Cl and NO2 provided high products yields (73ꢀ83% for 3b-3e). The employment of
4ꢀfluorobenzaldehyde led to compound 3f in 59% yield. Electronꢀdonating methoxy groups attached
to the aryl moiety decreased the yield to 37% (3g). When using benzaldehyde, the desired coupling
product 3u was not obtained although 1a was entirely consumed (the reaction afforded a complex
mixture). The investigation of the substrate scope by employing 2ꢀaminopyridines with electronꢀ
donating and ꢀwithdrawing groups in the reaction with unsubstituted benzaldehyde showed that the
electronic effects of substituents on the pyridine ring are not pronounced. Methyl and chloride
derivatives 3i and 3h were obtained in 23% and 14% yields, respectively.
The threeꢀcomponent coupling of 5ꢀhaloꢀ2ꢀaminopyridines with ethyl propiolate 1a and
benzaldehydes containing both electronꢀdonating and ꢀwithdrawing substituents on the benzoyl group
proceeded smoothly in 56ꢀ95% yield (3a,j-o). Weak electronꢀdonating pꢀtolylaldehyde showed
moderate yields (37%, 37% and 25% for 3n, 3p and 3q, respectively). However for pꢀ
ethylbenzaldehyde improvement was observed, compound 3r was isolated in 55% yield. The reaction
can also be performed with carboxyꢀsubstituted pyridines, namely, ethyl 2ꢀaminoisonicotinate,
producing the corresponding imidazo[1,2ꢀa]pyridines 3s,t in good yields.
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Table 2. Oneꢀpot synthesis of imidazo[1,2ꢀa]pyridines 3a,b
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a)Reaction conditions: step 1 ꢀ aldehyde 4 (0.36 mmol) and 2ꢀaminopyridine 5 (0.30 mmol) with molecular
sieves (300 mg) in toluene (1.5 mL) at 120 °C for 14h, step 2ꢀ ethyl propiolate 1a (2 equiv) and Cu(OAc)2
hydrate (10 mol %) at 120 °C for 1ꢀ3h. b) Isolated yield.
All these reactions were carried out at a 0.3 mmol scale; but they could easily be scaledꢀup. Indeed,
imidazo[1,2ꢀa]pyridine 3a was prepared in a 88% isolated yield (2.7 g, recrystallization from EtOH) at
the 8 mmol scale from 1.0 equiv (2.0 g) of the imine 2a.
The synthetic utility of the process described in this study was demonstrated by its use in a concise
route for the preparation of Alpidem, an anxyolytic drug (Scheme 2). Starting from the propiolamide
1b and Schiff base generated in situ from pꢀchlorbenzaldehyde 4b and 5ꢀchloroꢀ2ꢀaminopyridine 5b
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the target Alpidem 6 was produced. The isolated yield of 6 achieved in the oneꢀpot twoꢀstep procedure
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was 91% compared with the reported overall yields of 83% (two steps)16 and 72% (four steps).15
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Scheme 2. Synthesis of Alpidem
Control experiments were performed to gain insights on the reaction mechanism (Table 3). The
reaction of 1a with imine 2a under an inert atmosphere of argon under standard conditions for 2 hours
afforded 3a in 51% yield (Table 3, entry 2) versus 95% in air (Table 3, entry 1). Since the imine
alkynylation generally proceeds with Cu(I),16ꢀ21 the possibility of oxidative disproportionation of
Cu(II) as a source of active Cu(I) species was addressed with a mixed catalyst study. The direct
addition of Cu(I) as the CuCl salt (Table 3, entry 3) or the in situ generation of Cu(I) with an 2ꢀ
aminophenol26 additive (Table 3, entry 4) led to significant reduction of the 3a yield accompanied by
the formation of a complex mixture. More importantly, a comparison of the initial rate of the
formation of product 3a in experiments 1 and 3 (1H NMR monitoring, aliquots every 10ꢀ20 min,
corrected for the known amount of dibromomethane as the internal standard) showed that the CuCl
additive reduces the reaction rate (see Supporting information). Reaction acceleration was not
observed even at first reaction moment, prompting suggestions that copper(I) is not key reactive
species.
Table 3. Studies of the heterocyclization of propiolatesaꢀd
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entry
deviation from standard
yield
3a,%
conditions
1
2
ꢀ
95b
inert atmosphere
51c
5
6
7
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inert atmosphere,
CuCl (10 mol%)
75c
47c
3
inert atmosphere,
2ꢀaminophenol (5 mol%)
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aStandard reaction conditions: imine 2a (0.20
mmol), ethyl propiolate 1a (2 equiv), Cu(OAc)2
hydrate (10 mol %), toluene (1 mL) in a screwꢀ
b
с
capped vial under air.
Isolated yield.
Determined by 1H NMR with internal standard.d In
all experiments, the conversion of starting imine
2a was complete.
The possible mechanism for the formation of imidazo[1,2ꢀa]pyridines 3 by the reaction of Schiffꢀ
bases 2 with alkynes 1 suggested by literature precedents is shown in Scheme 3. The process is
initiated by the Cu(II)ꢀmediated aminomethylation of alkyne 1 with the Schiffꢀbaseꢀcopper complex27
leading to propargylamines 6. The subsequent cyclization of 6 into intermediate 7 and the
rearomatization of the former provides imidazo[1,2ꢀa]pyridines 3.19
Scheme 3. Proposed mechanistic pathway
In this case, most likely copper(II) alone provide the formation of propargylamines 625 in contrast to
mixed catalysis applying Cu(I) species. Moreover, the findings described above (Table 3) admit
transformations of 6 into 7 involving radical coupling processes via the aminyl radical28 either peroxyꢀ
copper(III) active species.24b
Conclusion:
In conclusion, we have explored the catalytic efficiency of an copper(II)ꢀ oxygen catalytic system in
the threeꢀcomponent coupling reaction of aryl aldehydes with 2ꢀaminopyridines and terminal alkynes
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towards imidazo[1,2ꢀa]pyridines. Unlike previous processes, the present practical method avoids the
requirement of an anaerobic procedure, uses inexpensive Cu(OAc)2 catalyst, tolerates an array of
functional groups and effective for propiolates derivateves. This simple, additiveꢀfree methodology
was successfully applied for the efficient synthesis of the anxiolytic drug Alpidem starting from
readily available starting materials.
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Experimental Section:
General Information
NMR spectra were acquired at room temperature; the chemical shifts δ were measured in ppm
relative to the solvent (1Н: CDCl3, δ = 7.27 ppm; 13C: CDCl3, δ = 77.00 ppm). Splitting patterns are
designated as s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; dd, double doublet; ddd, double
double doublet. The coupling constants (J) are in Hertz. The structures of all compounds were
established using 1D NMR (1H, 13C) spectroscopy. Highꢀresolution mass spectra (HRMS) were
obtained using electrospray ionization (ESI) with QꢀTOF detection and electron ionization (EI)
techniques. IR spectra were obtained either as potassium bromide pellets or as liquid films between
two potassium bromide pellets with an infrared spectrometer. Melting points (mp) are uncorrected.
Analytical thin layer chromatography (TLC) was carried out on silica gel plates (silica gel 60 F254
aluminum supported plates); the visualization was accomplished with an UV lamp (365 nm). Column
chromatography was performed on silica gel 60 (230ꢀ400 mesh) treated with 1% triethylamine
solution in petroleum benzene. Alkynes, aldehydes and 2ꢀaminopyridines were commercially
available and were used without additional purification. All reactions were carried out using freshly
distilled and dry solvents. Parent N,Nꢀdipropylpropiolamide was prepared according to published
procedures.29
General procedure for the synthesis of imidazo[1,2-a]pyridines 3.
A screwꢀcapped vial (2.0 mL) was charged with 2ꢀaminopyridine (0.3 mmol, 1.0 equiv), aldehyde
(0.36 mmol, 1.2 equiv), 4Å molecular sieves (300 mg) and dry toluene (1.5 mL, 0.5M). The
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microreactor was stirred at 120 C for 14h. The resulting mixture containing imine was cooled down
to room temperature and charged with Cu(OAc)2 hydrate (6 mg, 0.03 mmol, 10 mol % on anhydrous
basis) and alkyne (0.6 mmol, 2 equiv). The reaction mixture was stirred additionally at 120 oC for 1ꢀ3
h. Upon completion, the mixture was filtered through a plug of silica treated with 1% triethylamine
solution in petroleum benzene (eluent – EtOAc). The filtrate was concentrated under reduced pressure
to give a crude material, which was purified by column chromatography on silica gel to give product
(eluent: Et3N:EtOAc:petroleum ether).
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Ethyl 2-(6-chloro-2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)acetate (3a)
Yield 102 mg (95%), yellow solid, mp 154ꢀ162 °C; Rf = 0.32 (petroleum ether ꢀ EtOAc, 5:1). The
spectral data and melting point matched that reported by Ley and coworkers.14b 1H NMR (300 MHz,
CDCl3): δ 8.22 (s, 1H), 7.78 (d, J = 8.07 Hz, 2H), 7.64 (d, J = 9.53 Hz, 1H), 7.47 (d, J = 8.07 Hz, 2H),
7.25 (d, J = 9.53 Hz, 1H), 4.26 (q, J = 7.35 Hz, 2H), 4.00 (s, 2H), 1.31 (t, J = 7.35 Hz, 3H); 13C NMR
(75 MHz, CDCl3): δ 168.8 (CO), 144.4 (C), 143.4 (C), 134.3 (C), 132.1 (C), 129.8 (2×CH), 128.9
(2×CH), 126.2 (CH), 121.8 (CH), 120.9 (C), 117.9 (CH), 113.8 (C), 61.9 (CH2), 30.8 (CH2), 14.2
(CH3); IR (KBr) 3087 (s), 1727 (s), 1199 (s), 841 (w), 802 (w) сmꢀ1; MS (ESI) 348 [M]+.
Ethyl 2-(2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)acetate (3b)
Yield 76 mg (73%), yellow solid, mp 68ꢀ77 °C; Rf = 0.35 (petroleum ether ꢀ EtOAc, 1:1). The
spectral data and melting point matched that reported by Namboothiri and coworkers.15 1H NMR (300
MHz, CDCl3): δ 8.12 (d, J = 6.60 Hz, 1H), 7.79 (d, J = 8.07 Hz, 2H), 7.64 (d, J = 8.81 Hz, 1H), 7.43
(d, J = 8.07 Hz, 2H), 7.22 (dd, J = 6.50, 8.81 Hz, 1H), 6.85 (dd, J = 6.50, 6.60 Hz, 1H), 4.21 (q, J =
7.34 Hz, 2H), 3.99 (s, 2H), 1.26 (t, J = 7.34 Hz, 3H); 13C NMR (75 MHz, CDCl3): δ 169.2 (CO),
145.1 (C), 143.6 (C), 134.0 (C), 132.7 (C), 129.9 (2×CH), 128.9 (2×CH), 124.8 (CH), 123.8 (CH),
117.7 (CH), 113.1 (C), 112.6 (CH), 61.8 (CH2), 30.9 (CH2), 14.2 (CH3); IR (KBr) 3140 (w), 1728 (s),
1489 (s), 1198 (w) сmꢀ1; MS (ESI) 314 [M]+.
Ethyl 2-(2-(2,4-dichlorophenyl)imidazo[1,2-a]pyridin-3-yl)acetate (3c)
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Yield 79 mg (76%), yellow solid, mp 106ꢀ109 °C; Rf = 0.40 (petroleum ether ꢀ EtOAc, 2:1). 1H NMR
(300 MHz, CDCl3): δ 8.07 (d, J = 6.60 Hz, 1H), 7.67 (d, J = 9.50 Hz, 1H), 7.50ꢀ7.53 (m, 2H), 7.33ꢀ
7.37 (m, 1H), 7.23ꢀ7.28 (m, 1H), 6.90 (dd, J = 6.50, 6.60 Hz, 1H), 4.16 (q, J = 7.37 Hz, 2H), 3.86 (s,
2H), 1.23 (t, J = 7.37 Hz, 3H); 13C NMR (75 MHz, CDCl3): δ 169.0 (CO), 145.2 (C), 135.0 (C), 134.6
(2×C), 133.6 (CH), 132.0 (C), 129.7 (CH), 127.2 (CH), 124.7 (CH), 124.0 (CH), 118.0 (CH), 115.1
(C), 112.7 (CH), 61.6 (CH2), 30.6 (CH2), 14.2 (CH3); IR (KBr) 1729 (s), 1472 (s), 1205 (w), 1158 (w)
сmꢀ1; HRMS (ESI) 371.0328, calcd. for C17H14Cl2N2O2Na+ ([M+Na]+) 371.0325.
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Ethyl 2-(2-(3-nitrophenyl)imidazo[1,2-a]pyridin-3-yl)acetate (3d)
Yield 78 mg (75%), yellow solid, mp 103ꢀ109 °C; Rf = 0.40 (petroleum ether ꢀ EtOAc, 1:2). 1H NMR
(300 MHz, CDCl3): δ 8.79 (s, 1H), 8.22ꢀ8.28 (m, 3H), 7.64ꢀ7.72 (m, 2H), 7.31 (dd, J = 6.41, 8.50 Hz,
1H), 6.95 (dd, J = 6.05, 6.69 Hz, 1H), 4.28 (q, J = 7.59 Hz, 2H), 4.07 (s, 2H), 1.33 (t, J = 7.59 Hz,
3H); 13C NMR (75 MHz, CDCl3): δ 168.9 (CO), 148.7 (C), 145.2 (C), 142.0 (C), 135.8 (C), 134.6
(CH), 129.8 (CH), 125.6 (CH), 124.1 (CH), 123.3 (CH), 122.8 (CH), 117.8 (CH), 114.0 (C), 113.2
(CH), 62.2 (CH2), 31.0 (CH2), 14.2 (CH3); IR (KBr) 1730 (s), 1521 (w), 1346 (s), 753 (w) сmꢀ1; MS
(ESI) 325 [M]+; HRMS (ESIꢀTOF) 348.0949, calcd. for C17H15N3O4Na+ ([M+Na]+) 348.0955.
Ethyl 2-(2-(4-nitrophenyl)imidazo[1,2-a]pyridin-3-yl)acetate (3e)
Yield 87 mg (83%), yellow solid, mp 151ꢀ156 °C; Rf = 0.20 (petroleum ether ꢀ EtOAc, 2:1). 1H NMR
(300 MHz, CDCl3): δ 8.35 (d, J = 8.07 Hz, 2H), 8.21 (d, J = 6.60 Hz, 1H), 8.09 (d, J = 8.07 Hz, 2H),
7.77 (d, J = 8.80 Hz, 1H), 7.32ꢀ7.38 (m, 1H), 6.96ꢀ7.00 (m, 1H), 4.25 (q, J = 7.38 Hz, 2H), 4.06 (s,
2H), 1.30 (t, J = 7.38 Hz, 3H); 13C NMR (75 MHz, CDCl3): δ 168.9 (CO), 147.4 (C), 145.4 (C), 142.1
(C), 140.6 (C), 129.2 (2×CH), 125.7 (CH), 124.0 (3×CH), 118.0 (CH), 114.6 (C), 113.3 (CH), 62.1
(CH2), 31.0 (CH2), 14.3 (CH3); IR (KBr) 1734 (s), 1601 (s), 1509 (s), 1341 (s), 1234 (w), 734 (w) сmꢀ
1; MS (ESI) 325 [M]+; HRMS (ESIꢀTOF) 348.0960, calcd. for C17H15N3O4Na+ ([M+Na]+) 348.055.
Ethyl 2-(2-(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl)acetate (3f)
1
Yield 62 mg (59%), yellow oil; Rf = 0.30 (petroleum ether ꢀ EtOAc, 3:1). H NMR (300 MHz,
CDCl3): δ 8.09 (d, J = 6.61 Hz, 1H), 7.77ꢀ7.82 (m, 2H), 7.61 (d, J = 8.81 Hz, 1H), 7.10ꢀ7.21 (m, 3H),
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6.82 (dd, J = 6.48, 6.61 Hz, 1H), 4.18 (q, J = 7.34 Hz, 2H), 3.97 (s, 2H), 1.23 (t, J = 7.34 Hz, 3H); 13C
NMR (75 MHz, CDCl3): δ 169.4 (CO), 162.9 (d, JC-F = 246 Hz, C), 145.0 (C), 143.8 (C), 130.4 (d, JC-
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= 8 Hz, 2×CH), 124.8 (CH), 123.8 (CH), 117.7 (CH), 115.5 (d, JC-F = 21.1 Hz, 2×CH), 112.9 (C),
F
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112.6 (CH), 61.8 (CH2), 30.9 (CH2), 14.3 (CH3) (the signal of the one C atom was not observed); IR
(film) 3141 (w), 1733 (s), 1503 (s), 1223 (w), 844 (w) сmꢀ1; HRMS (ESIꢀTOF) 321.1015, calcd. for
C17H15FN2O2Na+ ([M+Na]+) 321.1010.
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Ethyl 2-(2-(2,4-dimethoxyphenyl)imidazo[1,2-a]pyridin-3-yl)acetate (3g)
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Yield 39 mg (37%), yellow oil; Rf = 0.16 (petroleum ether ꢀ EtOAc, 1:4). H NMR (300 MHz,
CDCl3): δ 8.16 (d, J = 6.60 Hz, 1H), 7.67 (d, J = 8.54 Hz, 1H), 7.47 (d, J = 1.47 Hz, 1H), 7.38 (dd, J =
1.47, 8.07 Hz, 1H), 7.23 (dd, J = 7.15, 8.54 Hz, 1H), 6.99 (d, J = 8.07 Hz, 1H), 6.87 (dd, J = 6.60,
7.15 Hz, 1H), 4.22 (q, J = 7.31 Hz, 2H), 4.04 (s, 2H), 3.98 (s, 3H), 3.94 (s, 3H), 1.27 (t, J = 7.31 Hz,
3H); 13C NMR (75 MHz, CDCl3): δ 169.6 (CO), 149.3 (C), 149.1 (C), 144.9 (C), 144.6 (C), 126.9 (C),
124.6 (CH), 123.8 (CH), 121.1 (CH), 117.5 (CH), 112.5 (CH), 112.0 (CH), 111.4 (CH), 110.1 (C),
61.7 (CH2), 56.1 (CH3O), 56.0 (CH3O), 31.1 (CH2), 14.3 (CH3); IR (film) 1732 (s), 1508 (s), 1397 (s),
+
1251 (w), 1025 (s), 753 (w) сmꢀ1; HRMS (ESIꢀTOF) 341.1498, calcd. for C19H21N2O4 ([M+H]+)
341.1496.
Ethyl 2-(6-chloro-2-phenylimidazo[1,2-a]pyridin-3-yl)acetate (3h)
Yield 14 mg (14%), yellow solid, mp 101ꢀ117 °C; Rf = 0.35 (petroleum ether ꢀ EtOAc, 1:1). The
spectral data and melting point matched that reported by Ley and coworkers.14b 1H NMR (300 MHz,
CDCl3): δ 8.22 (s, 1H), 7.83 (d, J = 7.34 Hz, 2H), 7.62 (d, J = 9.54 Hz, 1H), 7.47ꢀ7.52 (m, 2H), 7.39ꢀ
7.44 (m, 1H), 7.25 (d, J = 9.54 Hz, 1H), 4.26 (q, J = 7.34 Hz, 2H), 4.04 (s, 2H), 1.32 (t, J = 7.34 Hz,
3H); 13C NMR (75 MHz, CDCl3): δ 169.0 (CO), 145.7 (C), 143.4 (C), 133.7 (C), 128.7 (2×CH), 128.6
(2×CH), 128.2 (CH), 125.9 (CH), 121.8 (CH), 120.7 (C), 118.0 (CH), 113.7 (C), 61.8 (CH2), 30.8
(CH2), 14.2 (CH3); IR (KBr) 2966 (w), 1724 (s), 1198 (s), 1159 (s) сmꢀ1; MS (ESI) 314 [M]+.
Ethyl 2-(6-methyl-2-phenylimidazo[1,2-a]pyridin-3-yl)acetate (3i)
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Yield 24 mg (23%), yellow solid, mp 95ꢀ100 °C; Rf = 0.20 (petroleum ether ꢀ EtOAc, 3:1). The
spectral data and melting point matched that reported by Ley and coworkers.14b 1H NMR (300 MHz,
CDCl3): δ 7.89 (s, 1H), 7.83 (d, J = 7.34 Hz, 2H), 7.57 (d, J = 8.81 Hz, 1H), 7.44ꢀ7.49 (m, 2H), 7.34ꢀ
7.39 (m, 1H), 7.08 (d, J = 8.81 Hz, 1H), 4.23 (q, J = 7.34 Hz, 2H), 4.02 (s, 2H), 2.37 (s, 3H), 1.28 (t, J
= 7.34 Hz, 3H); 13C NMR (75 MHz, CDCl3): δ 169.5 (CO), 144.0 (C), 134.1 (C), 130.3 (C), 128.7
(3×CH), 127.9 (2×CH), 122.3 (CH), 121.5 (CH), 116.9 (CH), 112.8 (C), 108.1 (C), 61.7 (CH2), 30.9
(CH2), 18.5 (CH3), 14.2 (CH3); IR (KBr) 3148 (w), 1728 (s), 1180 (s), 796 (w), 702 (w) сmꢀ1; MS
(ESI) 294 [M]+.
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Ethyl 2-(6-chloro-2-(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl)acetate (3j)
Yield 63 mg (56%), yellow solid, mp 145ꢀ150 °C; Rf = 0.15 (petroleum ether ꢀ EtOAc, 3:1). 1H NMR
(300 MHz, CDCl3): δ 8.20 (s, 1H), 7.78ꢀ7.83 (m, 2H), 7.60 (d, J = 8.78 Hz, 1H), 7.15ꢀ7.22 (m, 3H),
4.25 (q, J = 7.34 Hz, 2H), 3.99 (s, 2H), 1.31 (t, J = 7.34 Hz, 3H); 13C (75 MHz, CDCl3): δ 169.0 (CO),
162.8 (d, JC-F = 247 Hz, C), 144.9 (C), 143.5 (C), 130.4 (d, JC-F = 9 Hz, 2×CH), 129.8 (C), 126.1 (CH),
121.9 (CH), 120.9 (C), 118.0 (CH), 115.7 (d, JC-F = 22.1 Hz, 2×CH), 113.5 (C), 62.0 (CH2), 30.9
(CH2), 14.3 (CH3); IR (KBr) 3131 (w), 1726 (s), 1501 (s), 1254 (w), 844 (w) сmꢀ1; HRMS (ESIꢀTOF)
+
333.0804, calcd. for C17H15ClFN2O2 ([M+H]+) 333.0801.
Ethyl 2-(6-chloro-2-(4-nitrophenyl)imidazo[1,2-a]pyridin-3-yl)acetate (3k)
Yield 75 mg (72%), yellow solid, mp 202ꢀ206 °C; Rf = 0.35 (petroleum ether ꢀ EtOAc, 3:1). 1H NMR
(300 MHz, CDCl3): δ 8.36 (d, J = 8.24 Hz, 2H), 8.26 (s, 1H), 8.06 (d, J = 8.24 Hz, 2H), 7.64 (d, J =
9.15 Hz, 1H), 7.27 (d, J = 9.15 Hz, 1H), 4.28 (q, J = 7.29 Hz, 2H), 4.05 (s, 2H), 1.33 (t, J = 7.29 Hz,
3H); 13C NMR (75 MHz, CDCl3): δ 168.6 (CO), 147.6 (C), 143.8 (C), 143.3 (C), 140.2 (C), 129.2
(2×CH), 127.0 (CH), 124.1 (2×CH), 122.0 (CH), 121.6 (C), 118.4 (CH), 115.1 (C), 62.3 (CH2), 31.0
(CH2), 14.3 (CH3); IR (KBr) 1722 (s), 1602 (s), 1514 (w), 1343 (w), 1212 (s), 860 (w) сmꢀ1; HRMS
+
(ESIꢀTOF) 360.0748, calcd. for C17H15ClN3O4 ([M+H]+) 360.0746.
Ethyl 2-(6-chloro-2-(2,4-dichlorophenyl)imidazo[1,2-a]pyridin-3-yl)acetate (3l)
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Yield 88 mg (84%), yellow solid, mp 141ꢀ146 °C; Rf = 0.20 (petroleum ether ꢀ EtOAc, 4:1). 1H NMR
(300 MHz, CDCl3): δ 8.13 (s, 1H), 7.63 (d, J = 9.54 Hz, 1H), 7.52 (s, 1H), 7.49 (d, J = 8.81 Hz, 1H),
7.35 (d, J = 8.81 Hz, 1H), 7.24 (d, J = 9.54 Hz, 1H), 4.18 (q, J = 7.39 Hz, 2H), 3.84 (s, 2H), 1.25 (t, J
= 7.39 Hz, 3H); 13C NMR (75 MHz, CDCl3): δ 168.6 (CO), 143.4 (C), 142.2 (C), 135.3 (C), 134.4 (C),
133.5 (CH), 131.2 (C), 129.9 (CH), 127.3 (CH), 126.4 (CH), 122.1 (CH), 121.2 (C), 118.2 (CH),
115.9 (C), 61.8 (CH2), 30.5 (CH2), 14.2 (CH3); IR (KBr) 3134 (s), 1725 (s), 1372 (s), 1325 (s), 1204
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(w), 1155 (w), 1100 (w), 808 (w) сmꢀ1; HRMS (ESIꢀTOF) 383.0121, calcd. for C17H14Cl3N2O2
+
([M+H]+) 383.0115.
Ethyl 2-(6-bromo-2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)acetate (3m)
Yield 73 mg (70%), yellow solid, mp 159ꢀ173 °C; Rf = 0.32 (petroleum ether ꢀ EtOAc, 5:1). 1H NMR
(300 MHz, CDCl3): δ 8.30 (s, 1H), 7.77 (d, J = 8.07 Hz, 2H), 7.55 (d, J = 8.81 Hz, 1H), 7.45 (d, J =
8.07 Hz, 2H), 7.30 (d, J = 8.81 Hz, 1H), 4.25 (q, J = 7.06 Hz, 2H), 3.99 (s, 2H), 1.30 (t, J = 7.06 Hz,
3H); 13C NMR (75 MHz, CDCl3): δ 168.9 (CO), 144.1 (C), 143.4 (C), 134.4 (C), 131.9 (C), 129.9
(2×CH), 129.1 (2×CH), 128.5 (CH), 124.1 (CH), 118.2 (CH), 113.7 (C), 107.6 (C), 62.0 (CH2), 30.9
(CH2), 14.2 (CH3); IR (KBr) 1724 (s), 1296 (w), 803 (w) сmꢀ1; MS (ESI) 393 [M]+; HRMS (ESIꢀ
TOF) 416.9790, calcd. for C17H14BrClN2O2Na+ ([M+Na]+) 416.9799.
Ethyl 2-(6-chloro-2-(p-tolyl)imidazo[1,2-a]pyridin-3-yl)acetate (3n)
Yield 39 mg (37%), yellow oil; Rf = 0.32 (petroleum ether ꢀ EtOAc, 5:1). The spectral data matched
that reported by Ley and coworkers.14b 1H NMR (300 MHz, CDCl3): δ 8.18 (s, 1H), 7.71 (d, J = 7.32
Hz, 2H), 7.59 (d, J = 9.54 Hz, 1H), 7.29 (d, J = 7.32 Hz, 2H), 7.19 (d, J = 9.54 Hz, 1H), 4.24 (q, J =
7.36 Hz, 2H), 4.01 (s, 2H), 2.41 (s, 3H), 1.30 (t, J = 7.36 Hz, 3H); 13C NMR (75 MHz, CDCl3): δ
169.1 (CO), 145.8 (C), 143.4 (C), 138.1 (C), 130.8 (C), 129.5 (2×CH), 128.5 (2×CH), 125.7 (CH),
121.8 (C), 120.6 (CH), 117.9 (CH), 113.4 (C), 61.8 (CH2), 30.9 (CH2), 21.3 (CH3), 14.2 (CH3); IR
(film) 1734 (s), 1573 (s), 1025 (w), 823 (w) сmꢀ1; MS (ESI) 328 [M]+.
Ethyl 2-(6-chloro-2-(2,4-dimethoxyphenyl)imidazo[1,2-a]pyridin-3-yl)acetate (3o)
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Yield 78 mg (75%), yellow oil; Rf = 0.38 (petroleum ether ꢀ EtOAc, 2:1). H NMR (300 MHz,
CDCl3): δ 8.25 (s, 1H), 7.66 (d, J = 9.54 Hz, 1H), 7.46 (s, 1H), 7.37 (d, J = 8.07 Hz, 1H), 7.24 (d, J =
9.54 Hz, 1H), 7.00 (d, J = 8.07 Hz, 1H), 4.25 (q, J = 7.46 Hz, 2H), 4.03 (s, 2H), 3.99 (s, 3H), 3.95 (s,
3H), 1.31 (t, J = 7.46 Hz, 3H); 13C NMR (75 MHz, CDCl3): δ 169.2 (CO), 149.3 (C), 146.4 (С), 145.7
(С), 143.3 (С), 126.4 (C), 125.8 (СH), 121.8 (CH), 121.0 (CH), 120.6 (C), 117.7 (CH), 113.1 (CH),
111.8 (C), 111.3 (CH), 61.9 (CH2), 56.0 (2×OCH3), 31.0 (CH2), 14.2 (CH3); IR (film) 3021 (w), 1734
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(s), 1509 (s), 1258 (w), 1102 (w) сmꢀ1; HRMS (ESIꢀTOF) 375.1099, calcd. for C19H20ClN2O4
+
([M+H]+) 375.1106.
Ethyl 2-(6-bromo-2-(p-tolyl)imidazo[1,2-a]pyridin-3-yl)acetate (3p)
1
Yield 39 mg (37%), yellow solid, mp 172ꢀ176 °C; Rf = 0.35 (petroleum ether ꢀ EtOAc, 4:1). H NMR
(300 MHz, CDCl3): δ 8.28 (s, 1H), 7.71 (d, J = 8.24 Hz, 2H), 7.54ꢀ7.57 (m, 1H), 7.27ꢀ7.30 (m, 3H),
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4.24 (q, J = 7.20 Hz, 2H), 4.01 (s, 2H), 2.41 (s, 3H), 1.30 (t, J = 7.20 Hz, 3H); C NMR (300 MHz,
CDCl3): δ 169.1 (CO), 145.3 (С), 143.3 (C), 138.3 (C), 130.4 (С), 129.6 (2×CH), 128.5 (2×CH),
128.2 (CH), 124.1 (CH), 118.1 (CH), 113.3 (C), 107.3 (C), 61.9 (CH2), 30.9 (CH2), 21.4 (CH3), 14.2
(CH3); IR (KBr) 3181 (w), 1731 (s), 1619 (w), 801 (w) сmꢀ1; HRMS (ESIꢀTOF) 395.0341, calcd. for
C18H17BrN2O2Na+ ([M+Na]+) 395.0366.
Ethyl 2-(6-methyl-2-(p-tolyl)imidazo[1,2-a]pyridin-3-yl)acetate (3q)
Yield 26 mg (25%), yellow solid, mp 85ꢀ99 °C; Rf = 0.20 (petroleum ether ꢀ EtOAc, 3:1). The spectral
data and melting point matched that reported by Namboothiri and coworkers.15 1H NMR (300 MHz,
CDCl3): δ 7.90 (s, 1H), 7.74 (d, J = 8.07 Hz, 2H), 7.62 (d, J = 8.80 Hz, 1H), 7.29 (d, J = 8.07 Hz, 2H),
7.11 (d, J = 8.80 Hz, 1H), 4.24 (q, J = 7.39 Hz, 2H), 4.02 (s, 2H), 2.41 (s, 3H), 2.38 (s, 3H), 1.29 (t, J
= 7.39 Hz, 3H); 13C NMR (75 MHz, CDCl3): δ 169.6 (CO), 144.5 (C), 144.0 (C), 137.6 (C), 131.4 (C),
129.4 (2×CH), 128.4 (2×CH), 127.6 (CH), 122.0 (C), 121.4 (CH), 116.8 (CH), 112.5 (C), 61.6 (CH2),
30.9 (CH2), 21.3 (CH3), 18.5 (CH3), 14.2 (CH3); IR (KBr) 3429 (w), 1722 (s), 1185 (w), 789 (w) сmꢀ1;
MS (ESI) 308 [M]+.
Ethyl 2-(2-(4-ethylphenyl)-6-methylimidazo[1,2-a]pyridin-3-yl)acetate (3r)
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Yield 57 mg (55%), yellow oil; Rf = 0.20 (petroleum ether ꢀ EtOAc, 3:1). H NMR (300 MHz,
CDCl3): δ 7.89 (s, 1H), 7.76 (d, J = 7.34 Hz, 2H), 7.57 (d, J = 8.81 Hz, 1H), 7.31 (d, J = 7.34 Hz, 2H),
7.08 (d, J = 8.81 Hz, 1H), 4.23 (q, J = 7.34 Hz, 2H), 4.02 (s, 2H), 2.71 (q, J = 7.34 Hz, 2H), 2.37 (s,
3H), 1.28 (t, J = 7.34 Hz, 6H); 13C NMR (75 MHz, CDCl3): δ 169.6 (CO), 144.5 (C), 144.1 (C), 144.0
(C), 131.6 (C), 128.6 (2×CH), 128.2 (2×CH), 127.6 (CH), 122.0 (C), 121.4 (CH), 116.9 (CH), 112.5
(C), 61.6 (CH2), 31.0 (CH2), 28.7 (CH3), 18.5 (CH3), 15.6 (CH3), 14.2 (CH3); IR (film) 1734 (s), 1252
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(w), 1027 (w), 839 (w) сmꢀ1; HRMS (ESIꢀTOF) 323.1763, calcd. for C20H23N2O2 ([M+H]+) 323.1754.
+
Ethyl 2-(4-carbometoxy-2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)acetate (3s)
Yield 68 mg (65%), yellow solid, mp 128ꢀ131 °C; Rf = 0.23 (petroleum ether ꢀ EtOAc, 2:1).1H NMR
(300 MHz, CDCl3): δ 8.38 (s, 1H), 8.17 (d, J = 7.47 Hz, 1H), 7.80 (d, J = 8.47 Hz, 2H), 7.46ꢀ7.49 (m,
3H), 4.24 (q, J = 7.43 Hz, 2H), 4.05 (s, 2H), 3.98 (s, 3H), 1.29 (t, J = 7.43 Hz, 3H); 13C NMR (75
MHz, CDCl3): δ 168.8 (CO), 165.7 (CO), 146.0 (C), 144.1 (C), 134.5 (C), 132.1 (C), 129.9 (2×CH),
129.0 (2×CH), 126.2 (C), 123.4 (CH), 120.3 (CН), 115.1 (C), 111.9 (СН), 62.0 (CH2), 52.7 (СН3),
30.9 (CH2), 14.2 (CH3); HRMS (ESIꢀTOF) 395.0756, calcd. for C19H17ClN2O4Na+ ([M+Na]+)
395.0769.
Ethyl 2-(4-carbometoxy-2-(4-nitrophenyl)imidazo[1,2-a]pyridin-3-yl)acetate (3t)
Yield 71 mg (68%), yellow solid, mp 161ꢀ164 °C; Rf = 0.20 (petroleum ether ꢀ EtOAc, 2:1). 1H NMR
(300 MHz, CDCl3): δ 8.39 (s, 1H), 8.35 (d, J = 7.82 Hz, 2H), 8.22 (d, J = 7.43Hz, 1H), 8.07 (d, J =
7.82 Hz, 2H), 7.52 (d, J = 7.43 Hz, 1H), 4.27 (q, J = 7.42 Hz, 2H), 4.10 (s, 2H), 3.98 (s, 3H), 1.31 (t, J
13
= 7.42 Hz, 3H); C NMR (75 MHz, CDCl3): δ 168.5 (CO), 165.5 (CO), 147.6 (C), 144.5 (C), 144.3
(C), 140.1 (C), 129.2 (2×CH), 126.9 (C), 124.1 (2×CH), 123.6 (CH), 120.5 (CН), 116.3 (C), 112.3
(СН), 62.2 (CH2), 52.8 (СН3), 31.0 (CH2), 14.2 (CH3); HRMS (ESIꢀTOF) 384.1184, calcd. for
C19H18N3O6 ([M+H]+) 384.1190.
+
2-(6-Chloro-2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)-N,N-dipropylacetamide (6)
Yield 95 mg (91%), yellow solid, mp 125ꢀ135 °C; Rf = 0.20 (petroleum ether ꢀ EtOAc, 3:1). The
spectral data and melting point matched that reported by Ley and coworkers.14b 1H NMR (300 MHz,
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CDCl3): δ 8.25 (d, J = 1.47 Hz, 1H), 7.58 (d, J = 8.07 Hz, 2H), 7.55 (d, J = 9.53 Hz, 1H), 7.43 (d, J =
8.07 Hz, 2H), 7.18 (dd, J = 1.47, 9.53 Hz, 1H), 4.05 (s, 2H), 3.30 (q, J = 7.34 Hz, 2H), 3.13 (q, J =
7.34 Hz, 2H), 1.48ꢀ1.59 (m, 4H), 0.86 (t, J = 7.34 Hz, 3H), 0.77 (t, J = 7.34 Hz, 3H); 13C NMR (75
MHz, CDCl3): δ 167.3 (CO), 143.8 (C), 143.6 (C), 134.2 (C), 132.8 (C), 129.9 (2×CH), 129.0 (2×CH),
126.1 (CH), 122.7 (CH), 120.6 (C), 117.8 (CH), 115.7 (C), 50.0 (CH2), 48.1 (CH2), 30.1 (CH2), 22.3
(CH2), 21.0 (CH2), 11.4 (CH3), 11.1 (CH3); MS (ESI) 404 [M+H]+.
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Associated content
Supporting Information Copies of 1H, 13C NMR spectra, full data concerning optimization of reaction
conditions and kinetic experiments are available in the supporting information. This material is
available free of charge via the Internet at http://pubs.acs.org.
Author information
Eꢀmail: yavolkova@gmail.com
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