Document Detail

Fluorescent property of 3-hydroxymethyl imidazo[1,2-a]pyridine and pyrimidine derivatives.
Jump to Full Text
MedLine Citation:
PMID:  22871219     Owner:  NLM     Status:  PubMed-not-MEDLINE    
Abstract/OtherAbstract:
BACKGROUND: Imidazo[1,2-a]pyridines and pyrimidines are important organic fluorophores which have been investigated as biomarkers and photochemical sensors. The effect on the luminescent property by substituents in the heterocycle and phenyl rings, have been studied as well. In this investigation, series of 3-hydroxymethyl imidazo[1,2-a]pyridines and pyrimidines were synthesized and evaluated in relation to fluorescence emission, based upon the hypothesis that the hydroxymethyl group may act as an enhancer of fluorescence intensity.
RESULTS: Compounds of both series emitted light in organic solvents dilutions as well as in acidic and alkaline media. Quantitative fluorescence spectroscopy determined that both fused heterocycles fluoresced more intensely than the parent unsubstituted imidazo[1,2-a]azine fluorophore. In particular, 3-hydroxymethyl imidazo[1,2-a]pyridines fluoresced more intensely than 3-hydroxymethyl imidazo[1,2-a]pyrimidines, the latter emitting blue light at longer wavelengths, whereas the former emitted purple light.
CONCLUSION: It was concluded that in most cases the hydroxymethyl moiety did act as an enhancer of the fluorescence intensity, however, a comparison made with the fluorescence emitted by 2-aryl imidazo[1,2-a]azines revealed that in some cases the hydroxymethyl substituent decreased the fluorescence intensity.
Authors:
Stephania Velázquez-Olvera; Héctor Salgado-Zamora; Manuel Velázquez-Ponce; Elena Campos-Aldrete; Alicia Reyes-Arellano; Cuauhtémoc Pérez-González
Related Documents :
15887469 - Cardiovascular function and basics of physiology in microgravity.
22444069 - Examining nocturnal railway noise and aircraft noise in the field: sleep, psychomotor p...
9418029 - The mechanics of flight in the hawkmoth manduca sexta. i. kinematics of hovering and fo...
24307469 - Inhibition by ethoxyzolamide of a photoacoustic uptake signal in leaves: evidence for c...
24658259 - Diel nitrogen fixation pattern of trichodesmium: the interactive control of light and ni.
23744779 - Varied response of western pacific hydrology to climate forcings over the last glacial ...
23367489 - Lower limb movement asymmetry measurement with a depth camera.
18342949 - Automated measurement of spatial preference in the open field test with transmitted lig...
18617179 - A mechanical supination sprain simulator for studying ankle supination sprain kinematics.
Publication Detail:
Type:  Journal Article     Date:  2012-08-07
Journal Detail:
Title:  Chemistry Central journal     Volume:  6     ISSN:  1752-153X     ISO Abbreviation:  Chem Cent J     Publication Date:  2012  
Date Detail:
Created Date:  2013-01-10     Completed Date:  2013-01-11     Revised Date:  2013-04-02    
Medline Journal Info:
Nlm Unique ID:  101314213     Medline TA:  Chem Cent J     Country:  England    
Other Details:
Languages:  eng     Pagination:  83     Citation Subset:  -    
Affiliation:
Departamento Química Orgánica, Escuela Nacional Ciencias Biológicas, Instituto Politécnico Nacional, México City,, Zip code 11340, , Mexico. hsalgado47@hotmail.com.
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms
Descriptor/Qualifier:
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

Full Text
Journal Information
Journal ID (nlm-ta): Chem Cent J
Journal ID (iso-abbrev): Chem Cent J
ISSN: 1752-153X
Publisher: BioMed Central
Article Information
Download PDF
Copyright ©2012 Velázquez-Olvera et al.; licensee Chemistry Central Ltd.
open-access:
Received Day: 22 Month: 3 Year: 2012
Accepted Day: 6 Month: 7 Year: 2012
collection publication date: Year: 2012
Electronic publication date: Day: 7 Month: 8 Year: 2012
Volume: 6First Page: 83 Last Page: 83
PubMed Id: 22871219
ID: 3541357
Publisher Id: 1752-153X-6-83
DOI: 10.1186/1752-153X-6-83

Fluorescent property of 3-hydroxymethyl imidazo[1,2-a]pyridine and pyrimidine derivatives
Stephania Velázquez-Olvera1 Email: steffivel@hotmail.com
Héctor Salgado-Zamora1 Email: hsalgado47@hotmail.com
Manuel Velázquez-Ponce2 Email: mapamanuel@hotmail.com
Elena Campos-Aldrete3 Email: camesol22@gmail.com
Alicia Reyes-Arellano3 Email: areyesarellano@yahoo.com.mx
Cuauhtémoc Pérez-González4 Email: cuaupegon@yahoo.com.mx
1Departamento Química Orgánica. Escuela Nacional Ciencias Biológicas, Instituto Politécnico Nacional, México City,, Zip code 11340, , Mexico
2Departamento de formación básica disciplinaria Instituto Politécnico Nacional. Mineral de Valenciana No 200 Fraccionamiento Industrial Puerto Interior 36275, Silao de la Victoria, Guanajuato, Mexico
3Departamento Química Orgánica. Escuela Nacional Ciencias Biológicas, Instituto Politécnico Nacional, México City, Zip code 11340, Mexico
4Departamento de Sistemas Biológicos. Universidad Autónoma Metropolitana Xochimilco, Mexico City, Zip code 23-181, Mexico

Background

In the past few years a growing interest in the chemistry of imidazo[1,2-a]pyrimidines and pyridines has been developed due to the extent of their applications in pharmacological science. Indeed they are known for their anxiolytic [1], cardiovascular [2], analgesic [3,4], antihypertensive [4] and neuroleptic [5,6] among other activities [7-9]. However, imidazo[1,2-a]pyridines and pyrimidines are also attractive due to their physicochemical properties exhibited, namely the fluorescent activity. Several studies concerning the effects of substituents on the fluorescent properties of imidazo[1,2-apyridines have been carried out, for instance, 2-phenyl (or 2-(2-naphthyl)) and/or 7-methyl substitution caused no deterioration of the fluorescent property. The amino or dimethylamino substitution at the 4'-position of 2-phenyl imidazo[1,2-apyridine shifted the fluorescence to the visible region in polar solvents [10]. From a comparative spectroscopy study performed on several imidazo[1,2-a]pyridines and pyrimidines, it was observed that substitution of a proton for methyl, carboxyl, or amino group increased the fluorescence intensity. Fluorescence was destroyed when a ring position carried a nitro group or when the pyridine or pyrimidine ring is catalytically reduced to the 5,6,7,8-tetrahydro derivative [11]. In the latter study, it was also observed that imidazo[1,2-a]pyrimidines fluoresced more intensely and ca. 60 nm higher than the analogous pyridines. Taking advantage of the fluorescence property, a imidazo1,2-a]pyridine derivative was used as a biomarker of hypoxic tumor cells [12]. A (4-piperidinylfluorophenyl) imidazo1,2-a]pyridine was applied to a multiple fluorescent chemosensor [13]. Recently, an imidazopyrimidine based compound was used in an electron transport layer of an organic light emission device [14].

However, a great disadvantage of many current fluorophores is their very short time of life and susceptibility to physicochemical environments [14], therefore interest in the development of more efficient fluorophores is growing. In this study, the hydroxymethyl group was investigated as an enhancer of the fluorescence property of derivatives of imidazo[1,2-a]pyridines and imidazo[1,2-a]pyrimidines with the aim of obtaining fluorophores with potential use as biomarkers.


Results and discussion

The hydroxymethyl group has proved to be a promoter of fluorescence in naphthyl thioureas [15]. In another study, it was reported that 2-(3,4,5,6-tetrafluoro-2-hydroxyphenyl)imidazo[1,2-a]pyridine emitted long wavelength light around 540 nm both in polar and in nonpolar solvents [16]. Based upon this information, it was hypothesized that introduction of a hydroxymethyl group at position 3 of the imidazo[1,2-a]azines should enhance fluorescence (probably through a spatial non-covalent interaction of the hydroxyl non-bonding electrons with the aryl rings) as compared to the parent fluorophore (the unsubstituted imidazo[1,2-a]azine).

The two series of compounds were prepared straightforward (Scheme 1). Condensation of 2-amino pyridine or 2-amino pyrimidine with the appropriately substituted 2-bromo acetophenone afforded the imidazo[1,2-a]azine nucleus. A Vilsmeier Haack treatment on the fused heterocycles 3 and 4 led to the corresponding 3-formyl substituted derivatives 5. Reduction of the formyl moiety with NaBH4 in alkaline ethyl alcohol delivered the 3-hydroxymethyl derivatives 6 and 7.

Some of these products are already known but have not been studied in relation to a fluorescence property. Products were fully identified by spectroscopic methods and were obtained in moderate to good yields as shown in Tables 1 and 2. New compounds were submitted to combustion analysis for complete characterization.

A series of qualitative assays aimed to evaluate the stability of the products and permanence of the fluorescent property followed: Compound 6 g did not fluoresce. Dilutions of the compounds (0.05 g) in common organic solvents (10 mL) such as ethyl alcohol, acetone, ethyl acetate, acetonitrile and dichloromethane showed fluorescence, this being considerably intense in ethyl acetate and dichloromethane. Solutions of 3-hydroxymethyl imidazo[1,2-a]pyridine 6 and pyrimidine 7 derivatives at various concentrations of aqueous HCl (0.1, 1 and 8 N) preserved the fluorescence, however, this was suppressed with 10 N HCl for the case of imidazo[1,2-a]pyrimidines 7 and deteriorated for the case of 6 at both λ 250 and 365 nm. Addition of weakly acidic materials also preserved fluorescence. Thus, heterogeneous 5% aqueous NH4Cl mixtures of 3-hydroxymethyl 6d showed a decreased fluorescence but 7d preserved it. A powdered mixture of silica gel (0.5 g), for column chromatography thoroughly mixed with the alcohol derivative 7d (10 mg) fluoresced only at the long wavelength λ 365 nm whereas 6d (10 mg) fluoresced at both wavelengths. These results indicate that the protonated species 8 holds the fluorescence activity to a certain extent. Fluorescence of both 6d and 7d in solutions 0.1, 1 and 10 N NaOH gradually diminished but prevailed at both wavelenghts. Biological materials such as egg yolk, pig blood, albumina and Giardia lamblia cultures were fluorescent upon addition of the imidazo[1,2-a]azines. The fluorescence of these products remained after several days.

The quantitative fluorescence analysis performed on one hundred-fold dilutions of the compounds showed that imidazo[1,2-a]pyridines absorbed and emitted energy at long wavelengths (Table 3) while imidazo[1,2-a]pyrimidines absorbed at lower wavelengths but emitted light at longer wavelengths (Table 4).

In the case of the imidazo[1,2-a]pyridines 6, all compounds fluoresced more intensely than the parent unsubstituted imidazo[1,2-a]pyridine 1, with the exception of the nitro substituted 6 g, which showed no fluorescence as was expected. It is also worth noting that the 2-(4-chlorophenyl) substituted imidazopyridine derivative 6b showed a rather low intensity.

As for the case of the imidazo[1,2-a]pyrimidine series, again the 2-(4’-chlorophenyl) substituted imidazopyrimidine 7b showed a very low intensity. Surprisingly, the electron donor substituted 7d and 7e and the nitro substituted derivative 7 g registered a similar intensity close to that given by the parent fluorophore 2.

A comparative UV absorption graph for both series of compounds is shown in Figure 1.

Figure 2 shows a comparison of the emission intensities. From these, it is clearly appreciated that imidazo[1,2-a]pyrimidines emitted light at longer wavelengths than analogous imidazo[1,2-a]pyridines but the latter fluoresced more intensely, in contrast to previous analyses on imidazo[1,2-a[azines [12]. The effects of the phenyl substituents on the outcome of the emission intensities did not follow a consistent pattern, some interesting results are worth pointing out. The strong electron-donating methoxy group caused a marked increased intensity on the imidazopyridine (6e) but not on the imidazopyrimidine (7e). The fluorescence intensity of the imidazo[1,2-a]azines with the phenyl carrying the electron-withdrawing chlorine was low in 6b and dramatically decreased in 7b, whereas the intensity of the derivative with the phenyl bearing the fluorine substituent, 7c was enhanced to make it the most fluorescent of the imidazopyrimidine series. Interestingly in the case of the 4’-nitrophenyl substituted imidazo[1,2-a]pyridine, fluorescence was completely absent, while in the 4’-nitrophenyl substituted imidazo[1,2-a]pyrimidine fluorescence did not vanish.

According to the previous results, the role of the hydroxymethyl moiety was not quite clear, therefore we decided to revise the influence of the aryl group on the luminescent response of the 2-aryl imidazo[1,2-a]azines. Results for the 2-aryl imidazo[1,2-a]pyridines 3 (Table 5) showed that the phenyl, as well as the 4’-chloro, 4’-fluoro and 4’-methoxy substituted phenyl increased the fluorescence intensity as compared to 1 and interestingly the 3,4-dimethoxyphenyl caused a drop-off of the intensity. In most cases, the hydroxymethyl group increased fluorescence intensity even more than the aryl substituent, therefore it acted as enhancer. However, the intensity was decreased in the 4’-fluoro substituted phenyl and even more in the case of the 4’-chloro substituted phenyl.

As for the case of imdazopyrimidines (Table 6), substitution by phenyl did increase the intensity as compared to the parent fluorophore 2, the 4’-nitro substituted phenyl did not show fluorescence and it was interesting to observe that the 4’-methoxy phenyl (4f) showed a very low intensity. With this information, it was concluded that the hydroxymethyl moiety was a promoter of fluorescence in compound (4 g) and acted as an enhancer of the intensity in all other derivatives except in 2-(4’-chlorophenyl) imidazo[1,2-a]pyrimidine where a decrement was found. Figure 3 shows a comparative graph of the emission wavelengths and fluorescence obtained for compounds 3 and 4.

Thermal properties

The thermal stability of the most fluorescent compounds, 6a, 6e, 6f, 7a, 7c and 7f was estimated through a thermo gravimetric analysis (TGA) within an interval 0 – 600°C under an inert atmosphere. From the TG curves shown in Figure 4 it was determined that these compounds were thermally stable up to 280°C. The thermodynamic most stable was 7f, which completely decomposed above 600°C (47.75% mass loss at 600°C). The chemically most stable was 6f (55.25% weight loss at 600°C) and compound 7a showed a 66.47% weight loss at 600°C, the least stable was 6a (95.25% weight loss at 600°C).

Experimental

Melting points were measured on an Electrothermal melting point apparatus and are uncorrected. The FT-IR spectra were recorded on Perkins-Elmer 257 spectrometer using KBr discs. 1 H and 13C nmr spectral data were recorded with a Varian Mercury 300 MHz or a Varian 500 spectrometer. The chemical shifts (δ) are referenced to internal (CH3)4Si (δ 1 H = 0, δ 13C = 0). Fluorescence measurements were performed with a Shimadzu spectrofluorophotometer (RF-5000), equipped with a 150-W Xenon lamp, 12” color video display, 1 x 1 cm quartz cells. Both, operational performance and instrument sensitivity were revised by running a Raman spectrum of methanol. Cells were mounted in the holding device. The cell was filled out with a dilution 1:100 of the compounds in question for various lengths and then washed four times with methanol. Thermo gravimetric analysis was performed on a TGA 2950 Thermogravimetric Analyzer TA Instruments in a range 0-600°C, at a rate of 10°C/min on a platinum tray, under a nitrogen atmosphere and a flux rate 37.5 and 25.

General procedure for the synthesis of 3-hydroxymethyl imidazo[1,2-a]pyridines and pyrimidines

In a round bottom flask equipped with a magnetic stirrer, 1 g of the formyl derivative was suspended in ethanol (30 mL). The mixture was heated to 30°C and NaBH4 dissolved in 2 mL of 0.1 N NaOH added (2 molar equivalents for imidazo[1,2-a]pyridine and 1 molar equivalent for imidazo[1,2-a]pyrimidine). The reaction mixture was left stirring and reaction progress monitored by thin layer chromatography. After completion, ethanol was removed under vacuum. The solid formed was re-suspended in water and concentrated HCl added dropwise to neutral pH. The solid was collected by filtration, washed with water and dried off with hexane.

2-Phenyl-3-hydroxymethy imidazo[1,2-a]pyridine 6a

IR υ max cm-1: 3290 (OH); 2966.57, 2916.51, 2848.34 (C-H); 1734.11 (C=C).

1H NMR (300MHz, DMSO-d6) δ: 8.46 (1H, dd, J5,6=6.9, J5,7=1.2, H5); 7.84 (2H, d, J2’,3’=6.9, H2’,6’); 7.61 (1H, dd, J8,7=8.1, J8,6=1.2, H8); 7.48 (2H, td, J3’,2’=6.9, J3’,4’=7.2, J3’,5’=1.6 H3’,H5’); 7.38 (1H, td, J4’,3’=7.2, J4’,2’=1.6 H4’); 7.3 (1H, td, J7,8=8.1, J7,6=6.9, J7,5=1.2, H7); 6.98 (1H, td, J6,5=6.9, J6,7=6.9, J6,8=1.2, H6); 5.44 (1H, s, OH); 4.92 (2H, s, CH2).

13C NMR (75.5MHz, DMSO-d6) δ: 143.9 (C5), 142.8 (C8a); 134.3 (C1’), 128.4 (C2’); 128.1 (C3’); 128.2 (C4’); 124.8 (C7); 120.4 (C3); 116.6 (C8); 111.9 (C6); 52.8 (CH2).

2-(4’-Chlorophenyl)-3-hydroxymethyl imidazo[1,2-a]pyridine 6b

Isolated as a white solid in 61.3% yield, mp 229 - 230ºC (Lit 15, mp >240°C).

IR υ max cm-1: 3398 (OH); 2930 (C-H); 1635 (C=C).

1H NMR (300MHz, DMSO-d6) δ: 8.46 (1H, d, J5,6=6.9, H5); 7.87 (2H, d, J2’,3’=8.8, H2’); 7.6 (1H, d, J8,7=9.0, H8); 7.52 (2H, d, J3’,2’=8.8, H3’,5’); 7.31 (1H, td, J7,8=9.0, J7,6=6.8, J7,5=1.2, H7); 6.98 (1H, td, J6,5=6.9, J6,7=6.8, J6,8=1.2, H6); 5.47 (1H, t, J=4.8, OH); 4.92 (2H, d, J=4.8, CH2).

13C NMR (125MHz, DMSO-d6) δ: 143.9 (C5); 142.8 (C8a); 134.3 (C1’); 128.4 (C2’); 128.1 (C3’); 128.2 (C4’); 125.0 (C2); 124.8 (C7); 120.4 (C3); 116.6 (C8); 111.9 (C6); 52.8 (CH2).

2-(4’-Fluorophenyl)-3-hydroxymethyl imidazo[1,2-a]pyridine 6c

Isolated as a white solid in 70.3% yield, mp 154 - 155ºC (Lit 15, mp 153 - 155°C).

IR υ max cm-1: 3427 (OH); 3137 and 3048 (C-H); 1600 (C=C).

1H NMR (300MHz, DMSO-d6) δ: 8.52 (1H, d, J5,6=6.9, H5); 8.0 (2H, dd, J2’,3’=9.0, Jm=5.7, H2’ and H6’); 7.57 (1H, d, J8,7=9.3, H8); 7.37 – 7.29 (3H, m, H7,3’,5’); 6.87 (1H, d, J6,5=6.9, H6); 5.54 (1H, s, OH); 4.91 (2H, s, CH2).

13C NMR (125MHz, DMSO-d6) δ: 163.4 and 161.0 (C4); 143.91 (C8a); 130.9 and 130.8 (C2); 125.1 (C1); 120.4 (C3); 116.6 (C8); 115.6 and 115.3 (C3); 112.1 (C6); 52.0 (CH2).

2-(4’-Methylphenyl)-3-hydroxymethyl imidazo[1,2-a]pyridine 6d

Isolated as a white solid in 76.7% yield, mp 274 - 275ºC (Lit 15, mp >290°C).

IR υ max cm-1: 3279 (OH); 3040 y aprox 2950 (C-H); 1654 (C=C).

1H NMR (500MHz, DMSO-d6) δ: 8.45 (1H, d, J5,6=6.9, H5); 7.74 (2H, d, J2’,3’=9.0, H2’,6’); 7.61 (1H, d, J8,7=9.3, H8); 7.33 – 7.28 (3H, m, H7,3’.5’); 6.98 (1H, dd, J6,5=6.9, J6,7=6.9, H6); 5.45 (1H, t, J=5.1, OH); 4.91 (2H, d, J=5.1, CH2); 2.36 (3H, s, CH3).

13C NMR (125MHz, DMSO-d6) δ: 143.9 (C5); 142.9 (C8a); 136.9 (C1’); 131.6 (C4’); 129.1 (C3’); 128.1 (C2’); 125.1 (C2); 124.9 (C7); 120.2 (C3); 116.5 (C8); 112.0 (C6); 52.2 (CH2); 20.8 (CH3).

2-(4’-Methoxyphenyl)-3-hydroxymethyl imidazo[1,2-a]pyridine 6e

Isolated as a white solid in 66.7% yield, mp 166 - 167ºC (Lit 15, mp 165 - 167°C).

IR υ max cm-1: 3427 (OH); ca. 2950 (C-H); 1610 (C=C).

1H NMR (300MHz, DMSO-d6) δ: 8.43 (1H, dd, J5,6=6.9, J5,7=1.5 H5); 7.77 (2H, d, J2’,3’=9.0, H2’,6’); 7.57 (1H, d, J8,7=9.0, H8); 7.28 (1H, td, J7,8=9.0, J7,6=6.6, J7,5=1.5, H7); 7.04 (2H, d, J3’,2’=9.0, H3’,5’); 6.95 (1H, d J6,7=6.6, H6); 5.37 (1H, d, J=5.1, OH); 4.9 (2H, d, J=5.1, CH2); 3.82 (3H, s, OCH3).

13C NMR (75.5MHz, DMSO-d6) δ: 157 (C4’); 141.9 (C5); 140.9 (C8a); 127.4 (C2’); 124.9 (C4); 123 (C1’); 122.7 (C2’); 117.8 (C3); 114.5 (C8); 112 (C3’); 109.8 (C6); 53.2 (CH2).

2-(3’,4’-Dimethoxyphenyl)-3-hydroxymethyl imidazo[1,2-a]pyridine 6f

Isolated as a brown solid in 71% yield, mp 171 - 172ºC (Lit 15, mp 170 - 172°C).

IR υ max cm-1: 3004.19 (OH); 2933.8 and 2834.93 (C-H); 1633.76 (C=C).

1H NMR (500MHz, DMSO-d6) δ: 8.46 (1H, d, J5,6=7.2 H5); 8.44 (1H, dd, J8,7=7.0, J8,6=1.6, H7); 7.61 (1H, d, J2’,6’=1.2, H2’); 7.56 (1H, dd, J6’,5’=6.4, J6’,2’=1.2 H6’); 7.50 (1H, dd, J7,8=7.0, J7,5=1.6 H7); 6.9 (1H, d, J5’,6’=8.0, H5’); 6.8(1H, td, J6,5=7.2, J6,7=7.2 J6,8=1.2 H6) ; 5.4 (1H, s, OH); 4.9 (2H, s, CH2); 3.83 (3H, s, OCH3), 3.81, (3H, s, OCH3).

13C NMR (125MHz, DMSO-d6) δ: 148.7 (C7); 148.5 (C4’); 143.7 (C3’); 142.9 (C8a); 127.03 (C2); 124.6 (C5); 120.4 (C1’); 119.8 (C6’); 116.4 (C3); 111.8 (C2’ and C5’); 111.7 (C6), 55.46 and 55.38 (OCH3); 52.1 (CH2).

2-(4’-Nitrophenyl)-3-hydroxymethyl imidazo[1,2-a]pyridine 6g

Isolated as a yellow solid in 70% yield, mp 225 - 226ºC (Lit 15, mp 224 - 226°C).

IR υ max cm-1: 3417 (OH); 3130, 2943 (C-H); 1600 (C = C).

1 H NMR (300 MHz, DMSO-d6) δ: 8.5 (1 H, d, J5,6 = 6.9); 8.49 (2 H, d, J2’,3’ = 8.9); 8.14 (2 H, d, J2’,3’ = 8.9); 7.62 (1 H, d, J7,8 = 9.0); 7.34 (1 H, ddd, J5,7 = 1.2, J6,7 = 6.9, J7,8 = 9.0); 7.0 (1 H, ddd, J6,8 = 1.2, J5,6 = 6.9, J6,7 = 6.9); 5.55 (1 H, t, J = 5.1, OH); 4.98 (2 H, d, J = 5.1, CH2).

13C NMR (125MHz, DMSO-d6) δ: 146.3 (C5); 144.2 (C8a); 140.8 (C1); 140.3 (C3); 128.6 (C3’); 125.4 (C4’); 125.0 (C2); 123.4 (C2’); 122.2 (C7); 116.8 (C8); 112.3 (C6); 52.0 (CH2).

2-Phenyl-3-hydroxymethyl imidazo[1,2-a]pyrimidine 7a

Isolated as a yellow solid in 60.6% yield, mp 241 - 242ºC.

IR υ max cm-1: 3216 (OH); 3082, 2948 y 2884 (C-H); 1614 (C=C).

1H NMR (300MHz, DMSO-d6) δ: 8.92 (1H, dd, J5,6=6.9, J5,7=1.2, H5); 7.84 (2H, d, J2’,3’=6.9, H2’,6’); 7.61 (1H, dd, J7,6=8.1, J7,5=1.2, H7); 7.53 (2H, dd, J3’,2’=6.9, J3’,4’=7.2, H3’,5’); 7.4 (1H, dd, J4’,3’=7.2, H4’); 7.1 (1H, td, J6,5=6.9, J6,7=6.9, J6,8=1.2, H6); 5.45 (1H, s, OH); 4.96 (2H, s, CH2).

13C NMR (75.5MHz, DMSO-d6) δ: 150.5 (C5), 147.2 (C8a); 143.6 (C1’), 133.8 (C2’); 128.6 (C3’); 128.3 (C4’); 128 (C7); 119.2 (C3); 108.6 (C8); 111.9 (C6); 51.8 (CH2).

Anal. calcd for C13H11N3O: C, 69.33 H, 4.88, N, 18.76; found: C, 69.41, H, 5.2, N, 18.46.

2-(4’-Chlorophenyl)-3-hydroxymethyl imidazo[1,2-a]pyrimidine 7b

Isolated as a yellow solid in 63.8% yield, mp 164 - 165ºC.

IR υ max cm-1: 3400 - 1900 (OH and C-H); 1662 and 1618 (C=C).

1H NMR (500MHz, DMSO-d6) δ: 8.97 (1H, d, J5,6=7.0, H5); 8.61 (1H, dd, J7,6=4.0, J7,5=2.0, H7); 7.91 (2H, d, J2’,3’=8.5, H2’,6’); 7.58 (2H, dd, J3’,2’=8.5, H3’,5’); 7.15 (1H, dd, J6,5=7.0, J6,7= 4.0, H6); 5.65 (1H, s, OH); 4.92 (2H, s, CH2).

13C- NMR (125MHz, DMSO-d6) δ: 150.6 (C7); 147.2 (C8a); 142.2 (C2); 133.6 (C5); 132.8 (C1’); 132.6 (C4’); 129.9 (C2’); 128.7 (C3’); 119.4 (C6); 108.7 (C3); 56.0 (CH2).

Anal. calcd for C13H10N3OCl: 60.11 H, 3.85, N, 16.19; found: C, 60.23, H, 4.01, N, 15.92.

2-(4’-Fluorophenyl)-3-hydroxymethyl imidazo[1,2-a]pyrimidine 7c

Isolated as a yellow solid in 30.3% yield, mp 232 - 233ºC.

IR υ max cm-1: 3300 (OH); 3076 (C-H); 1659 and 1615 (C=C).

1H NMR (500MHz, DMSO-d6) δ: 9.01 (1H, dd, J5,6=6.5, J5,7=2.0, H5); 8.59 (1H, dd, J7,6=4.0, J7,5=2.0, H7); 7.92 (2H, dd, J2’,3’=12.0, J2’F=5.0, H2’); 7.34 (2H, dd, J2’,3’=12.0, J3’F=9.0, H3’); 7.14 (1H, dd, J6,7=4.0, J6,5=6.5 H6); 5.72 (1H, s, OH); 4.9 (2H, s, CH2).

13C NMR (125MHz, DMSO-d6) δ: 163.4 and 161.0 (C4); 150.4 (C7); 147.0 (C8a); 142.4 (C2); 133.6 (C5); 130.2 (C2’); 130.1 (C1’); 119.2 (C6); 115.6 and 115.4 (C3’); 108.6 (C3); 51.5 (CH2).

Anal. calcd for C13H10N3OF: 64.19 H, 4.11, N, 17.28; found: C, 65.26, H, 4.23, N, 16.98.

2-(4’-Methylphenyl)-3-hydroxymethyl imidazo[1,2-a]pyrimidine 7d

Isolated as a yellow solid in 32% yield, mp 199 - 200ºC.

IR υ max cm-1: 3369 (OH); 2926 (C-H); 1617 (C=C).

1H NMR (500MHz, DMSO-d6) δ: 8.99 (1H, dd, J5,6=6.5, J5,7=1.5, H5); 8.59 (1H, dd, J7,6=7.0, J7,5=1.5, H7); 7.9 (2H, d, J2’,3’=8.0, H2’,6’) 7.57 (2H, d, J3’,2’=8.0, H3’,5’); 7.13 (1H, dd, J6,7=7.0, J6,5=6.5, H6); 5.7 (1H, s, OH); 4.91 (2H, s, CH2); 3.38 (3H, s, CH3).

13C NMR (125MHz, DMSO-d6) δ: 150.7 (C7); 147.1 (C8a); 142.2 (C2); 133.6 (C5); 132.7 (C1’); 132.7 (C4’); 129.8 (C3’); 128.6 (C2’); 119.6 (C6); 108.6 (C3); 55.9 (CH2); 51.5 (CH3).

Anal. calcd for C14H13N3O: 70.29 H, 5.39, N, 17.57; found: C, 70.13, H, 5.51, N, 17.38.

2-(4’-Methoxyphenyl)-3-hydroxymethyl imidazo[1,2-a]pyrimidine 7e

Isolated as a yellow solid in 86% yield, mp 187 - 188ºC.

IR υ max cm-1: 3409 (OH); aprox 2900 (C-H); 1617 (C=C).

1H NMR (500MHz, DMSO-d6) δ: 8.95 (1H, dd, J5,6=6.5, J5,7=2.0, H5); 8.56 (1H, dd, J7,6=4.0, J7,5=2.0, H7) 7.82 (2H, d, J2’,3’=8.5, H2’,6’); 7.12 (1H, dd, J6,5=6.5, J6,7=4.0, H6); 7.08 (2H, dd, J3’,2’=8.5, H3’,5’); 5.62 (1H, s, OH); 4.9 (2H, s, CH2); 3.83 (3H, s, OCH3).

13C NMR (125MHz, DMSO-d6) δ: 159.2 (C4’); 149.9 (C7); 147.1 (C8a); 143.6 (C2); 133.3 (C5); 129.5 (C2’); 118.4 (C6); 114.1 (C3’); 108.3 (C3); 55.2 (CH2) 51.7 (OCH3).

Anal. calcd for C14H13N3O2: 65.88 H, 5.09, N, 16.47; found: C, 65.66, H, 4.80, N, 16.29.

2-(3’,4’-Dimethoxyphenyl)-3-hydroxymethyl imidazo[1,2-a]pyrimidine 7f

Isolated as a brown solid in 30.4% yield, mp 200 - 201ºC.

IR υ max cm-1: 3397 (OH); 3083, 2994 and 2937 (C-H); 1615 (C=C).

1H NMR (500MHz, DMSO-d6) δ: 8.97 (1H, d, J5,6=4.0, H5); 8.56 (1H, d, J7,6=2.0, H7); 7.49 (1H, d, J2’,6’=2.0, H2’); 7.42 (1H, d, J6’,5’=8.0, H6’); 7.09 (2H, m, H5’,6); 5.46 (1H, s, OH); 4.93 (2H, s, CH2); 3.8 (6H, s, OCH3).

13C NMR (125MHz, DMSO-d6) δ: 149.9 (C7); 148.8 (C4’); 148.7 (C3’); 147.0 (C8a); 143.7 (C2); 133.3 (C5); 126.4 (C1’); 120.7 (C6’); 118.6 (C3); 111.8 (C2’ and C5’); 108.6 (C6), 55.5 and 55.4 (OCH3); 51.7 (CH2).

Anal. calcd for C15H15N3O3: 63.15 H, 5.26, N, 14.73; found: C, 63.01, H, 5.17, N, 14.44.

2-(4’-Nitrophenyl)-3-hydroxymethyl imidazo[1,2-a]pyrimidine 7g

Isolated as a yellow solid in 72% yield, mp 213 - 214ºC.

IR υ max cm-1: 3376 (OH); 2933 (C-H); 1675 (C=C).

1H NMR (300MHz, DMSO-d6) δ: 8.64 (1H, t, J5,6=6.9, J5,7=1.2, H5); 8.34 (2H, dd, J2’,3’=8.7, H3’); 8.15 (2H, d, J2’,3’=8.7, H2’); 7.1 (1H, dd, J6,8=1.2, J7,8=9.0, H8); 6.15 (1H, dd, J5,7=1.2, J6,7=6.6, J7,8=9.0, H7); 5.59 (1H, d, J6,8=1.2, H8); 4.9 (1H, t, J5,7=1.2, J6,7=6.6, J7,8=9.0, H7); 3.32 (1H, t, J5,6=6.9, J6,7=6.6, J6,8=1.2, H6); 2.9 (1H, d, J=5.1, OH); 2.4 (2H, d, J=5.1, CH2).

13C NMR (125MHz, DMSO-d6) δ: 152.7 (C5); 148.6 (C8a); 148.06 (C1); 142.3 (C3); 141.6 (C3’); 135.2 (C4’); 125.0 (C2); 130.3 (C2’); 125.2 (C7); 122.6 (C8); 110.3 (C6); 52.88 (CH2).

Anal. calcd for C13H10N4O3: 57.77 H, 3.70, N, 20.74; found: C, 57.56, H, 3.85, N, 20.62.


Conclusion

2-Aryl-3-hydroxymethyl imidazo[1,2-a]pyridines and 2-aryl-3-hydroxymethyl imidazo[1,2-a]pyrimidines emitted light at long wavelengths more intensely than the respective non-substituted imidazo[1,2-a]pyridine and pyrimidine fluorophores. The hydroxymethyl group was an enhancer of the fluorescence intensity of the 2-aryl imidazo[1,2-a]azines, although in some cases it caused a decrement of the luminescent activity. These findings indicate that an interplay of the electronic character of the phenyl substituents with the hydroxymethyl moiety is most probably operating. The thermogravimetric analysis on selected most fluorescent imidazo[1,2-a]azines, indicated that they are thermally stable up to 280°C. Other studies aimed to decide if the herein investigated compounds are suitable as effective fluorescent dyes in biological applications are currently underway.


Competing interests

The authors declare that they do not have competing interests.


Authors’ contributions

MVP observed high fluorescence activity when preparing 3-hydroxymethyl derivatives by reaction of the imidazo[1,2-a]pyridine with formaldehyde in an acidic media. HSZ proposed and designed the project. SVO confirmed the observation made by MVP, carried out the synthesis and characterization of all new compounds, and participated in both the qualitative and quantitative photophysical analysis. CPG, ARA and ECA contributed in the analysis of all spectral data and discussed with HSZ the course of the investigation. All authors read, made comments and approve the final manuscript.


Acknowledgements

We thank Consejo Nacional de Ciencia y Tecnología Mexico for financial support through project 49937. We are grateful to Dr. Armando Gómez Poyou, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México for the fluorometric measurements. Special thanks to Miguel Angel Canseco Martínez, Investigación en Materiales, Universidad Nacional Autónoma de México for the thermogravimetric study. SVO thanks Consejo Nacional de Ciencia y Tecnología for graduate scholarship No. 257526.


References
Dusza HP,Albright JD,U.S. 5, 037, 980(Cl. 544–281, CO 7D 487/ 04), 06 Aug. 1991 Appl. 182, 650, 18 Avr. 1988Chem AbstrYear: 1991115256202q
Okabe T,Bhooshan B,Novinson T,Hillyard IW,Garner GE,Robins RK,Dialkyl bicyclic heterocycles with a bridgehead nitrogen as purine analogs possessing significant cardiac inotropic activityJ Heterocyclic ChemYear: 19832073575110.1002/jhet.5570200345
Stachle H,Kummer W,Koppe H,Ger. Offen. 1974, 2, 234, 622 (Cl. CO 7D), 31 Jan. Appl. 22, 34622. 1, 14 Jun. 1972Chem AbstrYear: 197480120993z
Stachle H,Kummer W,Koppe H,Ger. Offen. 1983, DE 3, 124, 718(Cl. CO 7D 487/04), 13 Jan. Appl P 24 Jun. 1981Chem. AbstrYear: 1983114126153u
Stachle H,Kummer W,Koppe H,Ger. Offen. 1972, 2, 109, 524(Cl. CO7D), 07 Sep. Appl. 21 09524 9, 01 Mar.1971Chem AbstrYear: 197277164750 k
Yashiano T,Tadashi M,Eur. Pat. 1985, Appl. EP 163, 240 (Cl. CO 7D 487/ 04), 04 Dec, JP. Appl. 84/ 104, 257, 22 Mai.1984Chem AbstrYear: 1986104186438 t
El Kazzouli S,Griffon Du Bellay A,Berteina-Raboin S,Delagrange P,Caignard D-H,Guillaumet G,Design and synthesis of 2-phenylimidazo[1,2-a]pyridines as a novel class of melatonin receptor ligandsEur J Med ChemYear: 2011464252425710.1016/j.ejmech.2011.06.03021764185
Gong Y-D,Cheon HG,Lee T,Kang NS,A novel 3-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridine-2-yl)phenyl acetate skeleton and pharmacophore model as glucagon-like peptide 1 receptor agonistsBull Korean Chem SocYear: 2010313760376410.5012/bkcs.2010.31.12.3760
Koubachi J,El Kazzouli S,Berteina-Raboin S,Mouaddib A,Guillaumet G,Synthesis of polysubstituted imidazo[1,2-a]pyridines via microwave-assisted one-pot cyclization/Suzuki coupling/palladium-catalyzed heteroarylationJ Org ChemYear: 2007727650765510.1021/jo071260317784775
Tomoda H,Hirano T,Saito S,Mutai T,Araki K,Substituent Effects on Fluorescent Properties of Imidazo[1,2-a]pyridine-Based CompoundsBull Chem Soc JpnYear: 1999721327133410.1246/bcsj.72.1327
Rackham DM,Spectroscopic Studies of Some Imidazo[1,2-a]pyridine and Imidazo[1,2-a]pyrimidine DerivativesAppl SpectroscopyYear: 19793356156310.1366/0003702794925129
Hodgkiss RJ,Middleton RW,Parrick J,Rami HK,Wardman P,Wilson GD,Bioreductive fluorescent markers for hypoxic cells: A study of 2-nitroimidazoles with 1-substituents containing fluorescent, bridgehead-nitrogen, bicyclic systemsJ Med ChemYear: 1920199235
Kurushima T,Iwata S,Tanaka K,Application of (4-piperidinylfluorophenyl)imidazopyridine to a multiple fluorescence chemosensorNippon Kagakkai Koen YokoshuYear: 2006861473
Hee-Yeon K,Seung-Gak Y,Jung-Han S,Chang-Ho L,Hee-Joo K,Imidazopyrimidine-based compound and organic light-emitting device employing organic layer including the sameYear: 2008 US20080226945A1, 18 Sep.
Xuhong Q,Fengyu L,Promoting effects of the hydroxymethyl group on the fluorescent signaling recognition of anions by thioureasTetrahedron LettYear: 20034479579910.1016/S0040-4039(02)02671-0
Kiyoshi T,Tohru K,Satoru I,Syunsuke S,Fluorescent behavior of 2-(3,4,5,6-tetrafluoro-2-hydroxyphenyl)imidazo-[1,2-a]pyridine in the presence of metal perchlorateJ Heterocycl ChemYear: 20074430330710.1002/jhet.5570440204
Nilsson M,Haraldsson M,Henriksson S,Emond R,Savory E,Simpson I,Imidazopyridine CompoundsYear: 2010 WO2010064020A1, 10 Jun.
Anaflous A,Benchat N,Mimouni M,Abouricha S,Ben-Hadda T,El-Bali B,Hakkou A,Hacht B,Armed imidazo[1,2-a]pyrimidines (pyridines): Evaluation of antibacterial activityLett Drug Des DiscovYear: 2004122422910.2174/1570180043398885

Figures

[Figure ID: C1]
Scheme 1 

Synthesis of 3-hydroxymethyl imidazo[1,2-a]azines and structures 1, 2 and 8.



[Figure ID: F1]
Figure 1 

UV-Visible absorption spectra of imidazo[1,2-a]azines 6 and 7.



[Figure ID: F2]
Figure 2 

A comparison of emission wavelengths and intensity of imidazo[1,2-a]azines 6 and 7.



[Figure ID: F3]
Figure 3 

A comparison of emission wavelengths and fluorescence intensity for imidazo[1,2-a]pyridines 3 and imidazo[1,2-a]pyrimidines 4.



[Figure ID: F4]
Figure 4 

Thermogravimetric analysis of selected 3-hydroxymethyl imidazo[1,2-a]pyridine and pyrimidine derivatives.



Tables
[TableWrap ID: T1] Table 1 

Yields and melting points of 2-aryl-3-hydroxymethyl imidazo[1,2-a]pyridines 6


Compound 6 Aryl Yield (%) Mp (°C) Experimental Mp (°C) Literature*
a
C6H5
70%
202 - 203
>212
b
4’Cl-C6H4
61.3%
229 - 230
>240
c
4’F-C6H4
70.3%
154 - 155
153 - 155
d
4’CH3-C6H4
76.7%
274 - 275
>290
e
4’CH3O-C6H4
66.7%
166 - 167
165 - 167
f
3’,4’di-CH3O-C6H3
71%
171 - 172
170 - 172
g 4’NO2-C6H4 70% 225 - 226 224 – 226

* Reference [17].


[TableWrap ID: T2] Table 2 

Yields and melting points of 2-aryl-3-hydroxymethyl imidazo[1,2-a]pyrimidines 7


Compound 7 Aryl Yield (%) Mp (°C)
a
C6H5
60.6%
241 – 242*
b
4’Cl-C6H4
63.8%
164 - 165
c
4’F-C6H4
30.3%
232 - 233
d
4’CH3-C6H4
32%
199 - 200
e
4’CH3O-C6H4
86%
187 - 188
f
3’,4’di-CH3O-C6H3
30.4%
200 - 201
g 4’NO2-C6H4 72% 213 - 214

*Compound 2a is mentioned in reference [18], mp is not given.


[TableWrap ID: T3] Table 3 

Spectroscopic data for 2-aryl-3-hydroxymethyl imidazo[1,2-a]pyridines 6


 
UV / Vis
Fluorescence
Compound Aryl Absλ max(nm) λ ex (nm) λ em (nm) I*
1
---
318
320
376
101.9
6a
C6H5
320
320
381.6
346.91
6b
4’Cl-C6H4
323
320
381
147.17
6c
4’F-C6H4
320
320
380.4
340.42
6d
4’CH3-C6H4
323
320
381.2
306.31
6e
4’CH3O-C6H4
323
320
383.6
884.37
6f
3’,4’di-
CH3O-C6H3
323
320
385.6
878.18
6g 4’NO2-C6H4 347 347 - -

*I Fluorescence intensities were standardized to a Raman blank methanol solution.


[TableWrap ID: T4] Table 4 

Spectroscopic data for 2-aryl-3-hydroxymethyl imidazo[1,2-a]pyrimidines 7


 
 
UV / Vis
Fluorescence
Compound Aryl Absλ max(nm) λ ex (nm) λ em (nm) I*
2
---
229
230
414.8
205.58
7a
C6H5
247
247
437.6
432.44
7b
4’Cl-C6H4
228
228
439.2
53.56
7c
4’F-C6H4
240
240
437.2
542.19
7d
4’CH3-C6H4
240
240
433.6
184.23
7e
4’CH3O-C6H4
226
226
433.6
188.03
7f
3’,4’di-CH3O-C6H3
344
344
432.4
428.32
7g 4’NO2-C6H4 265 265 432 186.43

*I Fluorescence intensities were standardized to a Raman blank methanol solution.


[TableWrap ID: T5] Table 5 

Fluorescence data for 2-aryl imidazo[1,2-a]pyridines 3


 
R
UV / Vis
Fluorescence
Compound Aryl Absλ max(nm) λ ex (nm) λ em (nm) I*
1
---
318
320
376.0
101-9
3a
C6H5
237
240
375.6
367.8
3b
4’Cl-C6H4
245
245
375.2
310.92
3c
4’F-C6H4
300
300
374
470.34
3e
4’MeO-C6H4
315
315
381.6
407.83
3f 3’,4’diMeO- C6H3 228 230 385.6 178.19

*I Fluorescence intensities were standardized to a Raman blank methanol solution.


[TableWrap ID: T6] Table 6 

Fluorescence data for 2-aryl imidazo[1,2-a]pyrimidines 4


 
 
UV / Vis
Fluorescence
Compound Aryl Absλ max(nm) λ ex (nm) λ em (nm) I
2
---
229
230
414.8
205.58
4a
C6H5
237
240
429.2
351.98
4b
4’Cl-C6H4
245
245
428.4
334.1
4c
4’F-C6H4
240
240
431.6
355.16
4e
4’MeO-C6H4
240
240
439.2
303.01
4f
3’,4’diMeO-C6H3
222
222
447.6
55.998
4g 4’NO2-C6H4 352 352 --- ---

*I Fluorescence intensities were standardized to a Raman blank methanol solution.



Article Categories:
  • Research Article


Previous Document:  Determination of 10 ginsenosides in Panax ginseng of different harvest times based on HPLC fingerpri...
Next Document:  Sodium butyrate potentiates carbon tetrachloride-induced acute liver injury in mice.