Heteropolyacid-Containing Ionic Liquid-Catalyzed Multicomponent

Article Cite This: J. Org. Chem. 2018, 83, 4044−4053

pubs.acs.org/joc

Heteropolyacid-Containing Ionic Liquid-Catalyzed Multicomponent Synthesis of Bridgehead Nitrogen Heterocycles: Mechanisms and Mitochondrial Staining Haline G. O. Alvim,† Jose R. Correa,† José A. F. Assumpçaõ ,† Wender A. da Silva,† Marcelo O. Rodrigues,‡ Julio L. de Macedo,§ Mariana Fioramonte,∥ Fabio C. Gozzo,∥ Claudia C. Gatto,† and Brenno A. D. Neto*,† †

Laboratory of Medicinal and Technological Chemistry, University of Brasília, Chemistry Institute (IQ-UnB) and ‡LIMA-Laboratório de Inorgânica e Materiais, Campus Universitário Darcy Ribeiro, P. O. Box 4478, Brasília 70904-970, Distrito Federal, Brazil § Laboratory of Catalysis, Institute of Chemistry, University of Brasília (IQ-UnB), Brasilia 70910-900, Brazil ∥ Institute of Chemistry, Universidade Estadual de Campinas (Unicamp), 13083970, Campinas, SP, Brazil S Supporting Information *

ABSTRACT: The current manuscript describes the use of a heteropolyacid-containing task-specific ionic liquid, supported in imidazoliumbased ionic liquids, as the catalyst for an efficient multicomponent synthesis of hexahydroimidazo[1,2-α]pyridine derivatives. The reactions conditions were fully optimized, and the bridgehead nitrogen heterocycle derivatives could be obtained in just 1 h exclusively as a single isomer (trans). Single crystal X-ray analysis confirmed the trans derivative as the only isomer. The mechanism of the reaction was investigated by ESI(+)-MS(/MS), and the use of the elegant charge-tag strategy allowed a catalytic cycle to be proposed for the current transformation and revealed the possibility of at least two reaction pathways. One derivative bearing a coumarin scaffold was synthesized, and its fluorescent properties allowed it to be tested as a probe for live-cell imaging experiments with a preference for mitochondria.

■

INTRODUCTION

using 20 mol % of a Bronsted acid as the promoter, with ketone excess and typically in 24 h of reaction through a new multicomponent approach (Scheme 1).

The development of multicomponent reactions (MCRs) and their applications for one-pot production of several compounds with biological potential has fostered the synthetic toolbox expansion aiming at the access of bioactive compound libraries through diversity-oriented synthesis.1−4 The use of catalytic methodologies applied in MCRs has simplified an easier and straightforward access of new heterocyclic libraries of small molecules5 with huge potential for biological applications.1 Although MCRs have been regarded as “advanced tools for sustainable organic synthesis”,6 many have questioned their potential due to several drawbacks such as low yields, long reaction times, harsh conditions, requirement of reagents excesses, reproducibility issues, and others. Several classes of heterocycles have been successfully synthesized through the use of MCRs,7−10 as reviewed elsewhere.11−17 Natural and unnatural bridgehead nitrogen heterocycles, known to exhibit attractive biological activities for a plethora of their derivatives, may also be obtained through MCRs. Among these bridgehead nitrogen heterocycles, the class of hexahydroimidazo[1,2-a]pyridine derivatives (HImPs), however, has only recently been synthesized through a MCR approach.18 Landmark work of Hui and co-workers18 described the syntheses of HImPs © 2018 American Chemical Society

Scheme 1. Multicomponent Approach for the Synthesis of HImPsa

a

Note it is a four-component reaction.

Despite the pharmacological and biological potential expected for HImP derivatives, most of the available reports describe the biological properties of aromatic imidazopyridines,19−21 and saturated (or partially saturated) derivatives such as HImPs have been evaluated in only a few reports.22−24 All the biological potential of HImPs is indeed dormant especially due to the lack of a deep knowledge regarding their mechanisms of Received: February 18, 2018 Published: March 16, 2018 4044

DOI: 10.1021/acs.joc.8b00472 J. Org. Chem. 2018, 83, 4044−4053

Article

The Journal of Organic Chemistry Scheme 2. Model Reaction for the Synthesis of HImP 4a Catalyzed by MSI3PW

Table 1. Reaction Conditions for the Synthesis of HImP 4a using Benzaldehyde (1.00 mmol), Acetophenone (2.00 mmol), and Ethylenediamine (1.00 mmol) during a Time Period of 60 mina entry

catalyst (mol %)

solvent (1 mL)

temperature (°C)

yield (%)c

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23b

− 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 1 3 4 5 7 20

− H2O MeOH EtOH MeCN PhMe CH2Cl2 THF BMI·PF6 BMI·BF4 BMI·BF4 BMI·BF4 BMI·BF4 BMI·BF4 BMI·BF4 BMI·BF4 BMI·BF4 BMI·BF4 BMI·BF4 BMI·BF4 BMI·BF4 BMI·BF4 MeOH

70 70 70 70 70 70 70 70 70 70 40 50 60 70 80 90 100 70 70 70 70 70 70

9 19 21 11 14 15 15 5 12 31 17 19 22 31 32 29 10 23 51 67 91 60 90

Figure 1. Reaction profile on the synthesis of HImP 4a using MSI3PW as the catalyst and BMI·BF4 as the reaction medium.

a

The reactions were conducted in sealed Schlenk tubes to avoid solvent loss. bConditions and yield described elsewhere.18 Catalyst: p-toluenesulfonic acid; excess of acetophenone (2.50 mmol); 12 h of reaction. cIsolated yields.

actions and dynamics in live cells. Their preferred localization inside live cells remains unclear. Recently, there is an increasing interest in fluorescent adducts synthesized from MCRs approaches.25−30 These adducts have the potential to be applied in bioimaging experiments to depict their cellular dynamics and subcellular localization. In general, fluorescent MCRs derivatives only have their photophysical properties disclosed31−36 or are applied as fluorescent sensors.37−42 To the best of our knowledge, cell-imaging experiments have only been described for a few MCRs adducts43−45 such as those synthesized from the already fluorescent isonitrile-BODIPY scaffold.46 Based on our interest in MCRs47−49 and our interest in the development and application of fluorescent probes for bioimaging experiments,50,51 we describe herein a catalytic multicomponent synthesis of HImPs, including some fluorescent derivatives. An improved catalyzed version of the reaction in imidazolium ionic liquids and its mechanism is evaluated by

Figure 2. Molecular structure of HImP 4a with crystallographic labeling (30% probability displacement ellipsoids).

ESI(+)-MS(/MS). Bioimaging of one fluorescent derivative is also described.

■

RESULTS AND DISCUSSION With the knowledge and experience we developed using the acidic catalyst MSI3PW for different MCRs49,52 and catalysis in ionic liquids,53,54 we decided to investigate its use for HImPs syntheses (Scheme 2) under different reaction conditions. 4045


Article

The Journal of Organic Chemistry Table 2. HImP Derivatives Synthesized Using the Developed Conditionsa

a b

(70 °C, 1 mL of BMI·BF4, 60 min, MSI3PW 5 mol %, 1 mmol of the aldehyde, 1 mmol of ethylenediamine and 2 mmol of the ketone). N-2-Naphthyl-ethylenediamine (1 mmol) instead of ethylenediamine.

Only a few techniques were previously employed to characterize the known catalyst MSI3PW. In the Supporting Information (see Figures S1−S3) we have included additional characterization data such as elemental analyses, thermogravimetric analysis, TG/DTG/DTA, and XRD of the catalyst. Scheme 2 shows the model reaction used for the optimization of the catalytic tests toward HImP syntheses. The reactions conditions were optimized based on the results described in Table 1. For all tested conditions, no reagent excess was used toward a greener synthesis. 1-n-Butyl-3-methylimidazolium tetrafluoroborate (BMI·BF4) as the reaction medium returned the best result using 5 mol % of MSI3PW as the catalyst at 70 °C in only 60 min. Under the tested reaction conditions, no cis isomer could be noted, and only the trans isomer forms during the reaction, as noted by the NMR analyses. These results point to a positive ionic liquid effect55−58 over the reaction, although it has been described18 that the diastereoselectivities are already excellent (>20:1 by NMR) favoring the trans isomer in the absence of any ionic liquid. BMI·PF6 was not a good media because of anion decomposition, as already shown in the presence of MSI3PW.49

The reaction profile (yield vs time) was also evaluated under the optimized condition, and results are better visualized in Figure 1. It is depicted that the reaction reaches its maximum yield in only 60 min (91%), and after 120 min (89%) and 180 min (90%) the yield is basically the same as that obtained in 60 min. HImP 4a also afforded a crystal suitable for X-ray analysis (Figure 2). Tables S2 and S3 in the Supporting Information show the X-ray diffraction data collection and refinement parameters as well as selected bond distances (Å) and bond angles (deg) for HImP 4a. Several HImPs could be therefore synthesized using the optimized reaction conditions, and the results are visualized in Table 2. HImPs 4a−j were synthesized in good to excellent yields, and only the trans isomer was noted (by NMR). HImPs 4b−e were designed to incorporate coumarin fluorophores in their structures aiming at good fluorescence properties since coumarinbased fluorescent small-molecules are known to be good bioprobes, as reviewed elsewhere.59−61 The mechanism of the reaction, as the influence of the catalyst MSI3PW, was evaluated by electrospray (tandem) mass spectrometry (ESI-MS(/MS)). The polar and cationic nature 4046


Article

The Journal of Organic Chemistry

mixtures were previously heated (70 °C for 20 min) and then analyzed. The results obtained by using the charge-tagged aldehyde are better visualized in Figure 4. The experiment (Figure 4) allowed for the detection and characterization by MS/MS (Figure S4a−e) of important intermediates. Most of the ions noted in the ESI spectrum were fragments originated from the main intermediates, as noted in the spectra. Before the mechanistic proposition we also performed the ESI-MS(/MS) using the other two charge-tagged reagents under the same analysis conditions. The use of the charge-tagged ketone afforded interesting results (Figure 5) as well as the use of the charge-tagged chalcone (Figure 6). The detection of key intermediates and their characterization by MS/MS (Figure S5a−e) allowed for a proposition of an accurate mechanism for the reaction (Scheme 3). The proposed catalytic cycle is in accordance with the original prediction of Hui and co-workers.18 The acetophenone protonation affords intermediate Ia which reacts with ethylenediamine to form IIa. A second acetophenone molecule is then condensed affording IIIa (enamine tautomer). The aldehyde is next incorporated to give intermediate IVa which in turn (intramolecular enamine reaction) is converted into the final HImP adduct. Although it is an accurate proposition, the detected intermediates allowed for an alternative mechanism as well, as shown in Scheme 4. It is not possible, with the current available data, to suggest the preferred reaction pathway, but both mechanisms seem to be plausible and, as expected for most multicomponent reactions, the final adduct is the same, regardless of the reaction pathway. The alternative proposition also explains the possibility of using a chalcone derivative to afford the desired HImP derivative in a three component version of the MCR. The synthetic procedure starting with a chalcone, acetophenone, and

of the derivatives should favor an efficient “fishing” of these intermediates.62−64 ESI proved indeed to be an outstanding tool to online monitoring of the formed intermediates (also for transient intermediates)65 and adducts.66 Both the gentle and fast transfer of the in situ formed intermediates allow for a continuous snapshots of the solution ionic composition affording useful information regarding the mechanism of the online monitored reaction. To improve the detection and characterization of transient and low abundant intermediates, the elegant strategy of charge tags has been developed.67−69 The strategy is based on the incorporation of a natural charge on the reagents structures which in turn afford charged (transient) intermediates facilitating their detection and characterization.70 We have successfully used this strategy to monitor several catalyzed and noncatalyzed reactions.47,48,53,71 In this context, we have used three different charge-tagged reagents (Figure 3) to probe the mechanism of the catalyzed

Figure 3. Charge-tagged reagents used in the current study. The charge-tagged reagents were tested separately to avoid the formation of dicharged (less stable) intermediates.

reaction. We have already reported the MSI3PW characterization by ESI-MS(/MS) elsewhere.49,52 The online monitoring by ESI(+)-MS(/MS) of the (fourcomponent) multicomponent reaction allowed us to detect and characterize several important intermediates. First, an equimolecular mixture (50 μM each reagent in MeOH) of the charge-tagged aldehyde, acetophenone, and ethylenediamine was monitored in the presence of MSI3PW (5 μM). All reaction

Figure 4. High-resolution ESI(+)-MS monitoring the multicomponent reaction by mixing the charge-tagged aldehyde, acetophenone, ethylenediamine, and MSI3PW. Note the key intermediates and adduct highlighted in the inset. 4047


Article


Figure 5. High-resolution ESI(+)-MS monitoring the multicomponent reaction by mixing the charge-tagged ketone, benzaldehyde, ethylenediamine, and MSI3PW. Note the key intermediates and adduct highlighted in the inset.

Figure 6. High-resolution ESI(+)-MS monitoring the multicomponent reaction by mixing the charge-tagged chalcone, acetophenone, ethylenediamine, and MSI3PW. Note the key intermediates and adduct highlighted in the inset.

are also noted. Small variation is noted at their absorption maxima (Δλ = 8 nm) indicating almost no charge transfer at the ground state. Their emission maxima are in the blue to green regions, and they proved to be intense. Regardless of the solvent used, the large distance between the emission and absorption wavelengths indicates an easy adjustment of the confocal microscopy to perform the bioimaging experiments. The use of 4e in live cell-imaging experiments (Figure 7) indeed returned interesting results. HImP 4e emitted an intense green fluorescence inside breast cancer cells (MCF-7). Both live and fixed cells returned similar results. The probe showed an accumulation near to the cells’

ethylenediamine indeed afforded the HImP, but with lower yields than those obtained by using the four component approach. Finally, we decided to test one fluorescent derivative as a live cell fluorescence imaging probe. We randomly chose HImP 4e to disclose their potential as live cell imaging probes. The photophysical characterization of 4e was then performed, and results are summarized in Table 3. Figures S6 shows the spectra of the different solvents and the solvatochromic effect observed for the new compound. It is noted large Stokes’ shifts for all tested solvents and values were in the range of 105−194 nm. Large molar extinction coefficients (log ε values in the range of 3.78−4.26 mM−1 cm−1) 4048


Article

The Journal of Organic Chemistry Scheme 3. Catalytic Cycle for the Formation of Hexahydroimidazo[1,2-a]pyridine Derivatives under Acid Catalysis

nuclei, a region known to be mitochondria rich,72 therefore indicating a preference toward mitochondria. The morphology and distribution of 4e also point firmly to this preference for mitochondria. In summary, a catalytic and efficient MCR methodology was developed to a rapid access of hexahydroimidazo[1,2-a]pyridine derivatives. The use of a heteropolyacid-containing task-specific ionic liquid as the catalyst allowed the synthesis of 10 new derivatives exclusively in the trans configuration and in a short time period. The use of the elegant charge tag strategy allowed us to depict two concurrent mechanisms, but the same final adduct could be obtained. The incorporation of coumarin scaffolds in the structure of 4e made the dye prone to be used as a live-cell imaging probe. The use of the new compound in bioimaging showed the MCR adduct had a preference for mitochondria.

■

This instrument has a hybrid quadrupole/ion mobility/orthogonal acceleration time-of-flight (oa-TOF) geometry and was used in the TOF V+ mode. All samples were dissolved in methanol to form 50 μM solutions and were directly infused into the ESI source at a flow rate of 10 μL/min after 5 min at 80 °C. ESI source conditions were as follows: capillary voltage 3.0 kV, sample cone 20 V, extraction cone 3 V. NMR spectra were recorded on a 7.05 T instrument using a 5 mm internal diameter probe operating at 600 MHz for 1H and at 150 MHz for 13C. Chemical shifts were expressed in parts per million (ppm) and referenced by the signals of the residual hydrogen atoms of the deuterated solvent, as indicated in the legends. Melting points were recorded using a sealed capillary tube. General Procedure for the Multicomponent Reaction of Hexahydroimidazo[1,2-a] Pyridines (HImPs). In a Schlenk tube was added 1.00 mmol of the aldehyde, 2.00 mmol of the ketone, and 1.00 mmol of ethylenediamine, 5 mol % of MSI3PW, and 1 mL of BMI·BF4. The mixture was kept at 70 °C under stirring for 60 min. The catalyst MSI3PW was then removed by filtration in Celite/ alumina system using ethyl acetate as the eluent. The organic solvent was removed, and the HImPs were purified by solvent crystallization (ethanol for 4a,e−g; water for 4h and acetone for 4i). HImPs 4b−d

EXPERIMENTAL SECTION

General. ESI-MS and ESI-MS/MS measurements were performed in the positive ion mode (m/z 50−2000 range) on a HDMS instrument. 4049


Article


Scheme 4. Alternative Catalytic Cycle for the Formation of Hexahydroimidazo[1,2-a]pyridine Derivatives under Acid Catalysis

C NMR (CDCl3,150 MHz) δ ppm 39.1, 41.5, 44.2, 52.3, 80.6, 107.5, 125.9, 126.2, 127.2, 127.4, 128.3, 128.4, 139.6, 144.7, 145.4, 145.7. Anal. calcd for C25H24N2 C, 85.19; H, 6.86; N, 7.95; Found C, 85.28; H, 6.98; N, 8.12. Yield: 91% (320 mg). 3,3′-((7R,8aS)-7-(4-(Dimethylamino)phenyl)-1,2,3,7,8,8ahexahydroimidazo[1,2-a]pyridine-5,8a-diyl)bis(2H-chromen2-one) (HImP 4b). Red solid, mp 214−215 °C. 1H NMR (DMSOd6, 600 MHz) δ ppm 1.04 (t, J = 6.97 Hz, 1H), 2.98 (s, 5H), 3.01 (s, 3H) 6.72−6.77 (m, 4H), 7.32−7.45 (m, 5H), 7.54−7.56 (m, 2H), 7.64−7.72 (m, 5H), 7.86 (d, J = 7.70 Hz, 1H), 8.52 (s, 1H), 9.63 (s, 1H). 13C NMR (DMSO-d6,150 MHz) δ ppm 18.9, 28.3, 40.1, 56.6, 111.5, 112.3, 116.6, 119.2, 121.9, 125.4, 130.6, 131.3, 134.4, 146.3, 146.6, 152.8, 154.8, 159.1, 187.2, 190.6. Anal. calcd for C33H29N3O4 C, 74.56; H, 5.50; N, 7.90; Found C, 74.67; H, 5.61; N, 8.04. Yield: 83% (441 mg). 3,3′-((7R,8aS)-7-(Benzo[d][1,3]dioxol-5-yl)-1,2,3,7,8,8ahexahydroimidazo[1,2-a]pyridine-5,8a-diyl)bis(2H-chromen2-one) (HImP 4c). Yellow solid, decomposition at 270 °C. 1H NMR (DMSO-d6, 600 MHz) δ ppm 1.18 (t, J = 7.34 Hz, 1H), 1.99 (s, 1H), 2.81−2.92 (m, 3H), 4.38 (d, J = 6.24 Hz, 1H), 5.88 (d, J = 6.97 Hz, 2H) 6.67−6.70 (m, 2H), 6.75 (s, 1H), 6.92 (t, J = 4.40 Hz, 1H), 7.12 (d, J = 2.57 Hz, 1H), 7.15 (t, J = 5.50 Hz, 1H), 7.33−7.38 (m, 2H), 7.59 (t, J = 6.97 Hz, 1H), 7.75 (d, J = 7.70 Hz, 1H), 8.15 (s, 1H) 13 C NMR (DMSO-d6, 150 MHz) δ ppm 20.9, 34.4, 37.7, 40.2, 42.7, 13

Table 3. Photophysical Data (in Different Solvents) for 4e (10 μM for All Analyses) compound

4e

solvent (dipolar moment - D)

λmax(abs) (nm)

log ε

λmax em (nm)

Stokes shift (nm)

toluene (0.36) CHCl3 (1.04) CH2Cl2 (1.60) ethanol (1.69) methanol (1.70) H2O (1.85) CH3CN (3.92) DMSO (3.96)

345 342 344 342 337 337 342 340

3.90 4.26 4.18 3.78 3.95 4.20 4.20 4.00

465 534 538 465 449 505 447 455

120 192 194 123 112 168 105 115

crude products were purified by using alumina chromatography column eluted with mixtures of dichloromethane and ethyl acetate (typically 1:3 v:v). (7R,8aS)-5,7,8a-Triphenyl-1,2,3,7,8,8a-hexahydroimidazo[1,2-a]pyridine (HImP 4a). White solid, mp 134−135 °C. 1H NMR (CDCl3, 600 MHz) δ ppm 1.89 (t, J = 12.47 Hz, 1H), 2.47 (ddd, J = 12.10, 5.87, 1.10 Hz, 1H), 2.97−3.02 (m, 2H), 3.08−3.18 (m, 2H), 3.61 (dt, J = 9.17, 6.70, 1H), 5.00 (m, 1H), 7.20−7.23 (m, 1H), 7.27 (m, 1H), 7.29−7.36 (m, 5H), 7.40−7.41 (m, 4H), 7.65−7.71 (m, 4H). 4050


Article


4-((7R,8aS)-5,8a-Diphenyl-1,2,3,7,8,8a-hexahydroimidazo[1,2-a]pyridin-7-yl)-N,N-dimethylaniline (HImP 4g). White solid, mp 174−175 °C. 1H NMR (CDCl3, 600 MHz) δ ppm 1.85 (t, J = 12.47 Hz, 1H), 2.43 (dd, J = 12.47, 5.50 Hz, 1H), 2.88−2.98 (m, 8H), 3.05-3.17 (m, 2H), 3.59 (dt, J = 9.17, 6.60 Hz, 1H), 4.99 (s, 1H), 6.70 (d, J = 8.44 Hz, 2H), 7.12 (d, J = 8.44 Hz, 1H), 7.32 (q, J = 14.31, 7.34 Hz, 2H), 7.38 (t, J = 6.97 Hz, 4H), 7.66 (dd, J = 7.34, 20.91 Hz, 4H). 13 C NMR (CDCl3, 150 MHz) δ ppm 38.1, 40.9, 41.5, 44.22, 52.3, 80.7, 108.7, 113.0, 126.0, 127.2, 127.4, 127.8, 128.0, 128.2, 128.3, 133.41, 139.8, 145.1, 145.3, 149.4. Anal. calcd for C27H29N3 C, 81.99; H, 7.39; N, 10.62; Found C, 82.08; H, 7.48; N, 10.75. Yield: 73% (288 mg). (7R,8aS)-7-(3-Nitrophenyl)-5,8a-diphenyl-1,2,3,7,8,8ahexahydroimidazo[1,2-a]pyridine (HImP 4h). Red solid, mp 112−113 °C. 1H NMR (CDCl3, 600 MHz) δ ppm 1.87 (t, J = 12.10 Hz, 1H), 2.48 (ddd, J = 12.47, 5.50, 1.47 Hz, 1H), 3.03-3.18 (m, 4H), 3.60 (dt, J = 9.54, 6.60 Hz, 1H), 4.88 (s, 1H), 7.33−7.37 (m, 2H), 7.40−7.46 (m, 5H), 7.56 (d, J = 7.70 Hz, 1H), 7.66 (dd, J = 20.17, 6.97 Hz, 4H), 8.07 (ddd, J = 8.07, 2.20, 1.10 Hz, 1H), 8.14 (t, J = 1.83 Hz, 1H). 13C (CDCl3, 150 MHz) δ ppm 39.0, 41.6, 44.2, 52.2, 80.6, 104.9, 121.5, 122.3, 125.8, 127.3, 127.8, 128.3, 128.4, 128.6, 129.2, 133.9, 139.2, 144.3, 146.9, 147.7, 148.5. Anal. calcd for C25H23N3O2 C, 75.54; H, 5.83; N, 10.57; Found C, 75.67; H, 5.99; N, 10.71. Yield: 70% (278 mg). 4-((7R,8aS)-5,8a-Diphenyl-1,2,3,7,8,8a-hexahydroimidazo[1,2-a]pyridin-7-yl)-2-methoxyphenol (HImP 4i). Brown solid, mp 182−184 °C. 1H NMR (CDCl3, 600 MHz) δ ppm 1.86 (t, J = 12.3 Hz, 1H), 2.44 (ddd, 12.10, 6.60, 1.10 Hz, 1H), 2.91 (ddd, J = 12.10, 5.50, 1.83 Hz, 1H), 2.99 (ddd, J = 9.17, 6.97, 5.14 Hz, 1H), 3.07−3.17 (m, 2H), 3.59 (dt, 9.17, 6.60 Hz, 1H), 3.86 (s, 3H), 4.95 (s, 1H), 6.71 (d, J = 1.83 Hz, 1H), 6.76 (dd, J = 8.07, 1.83 Hz, 1H), 6.87 (d, J = 8.07 Hz, 1H), 7.31−7.34 (m, 2H), 7.39 (t, 8.07 Hz, 4H), 7.64−7.68 (m, 5H). 13C NMR (CDCl3, 150 MHz) δ ppm 38.8, 41.6, 44.2, 52.2, 56.0, 80.7, 107.9, 110.2, 114.4, 119.8, 125.9, 127.2, 127.5, 127.9, 128.3, 128.4, 128.7, 129.1, 137.3, 139.6, 144.0, 144.9, 145.5, 146.4. Anal. calcd for C26H26N2O2 C, 78.36; H, 6.58; N, 7.03; Found C, 78.45; H, 6.69; N, 7.15. Yield: 55% (219 mg). (7R,8aS)-7-(Benzo[d][1,3]dioxol-5-yl)-5,8a-diphenyl1,2,3,7,8,8a-hexahydroimidazo[1,2-a]pyridine (HImP 4j). White solid, mp 143−144 °C. 1H NMR (CDCl3, 600 MHz) δ ppm 1.75 (t, J = 12.5 Hz, 1H), 2.34 (ddd, 12.10, 5.50, 1.10 Hz, 1H), 2.82 (ddd, J = 12.10, 5.50, 2.20 Hz, 1H), 2.89−2.92 (m, 1H), 3.00−3.10 (m, 2H), 3.51 (dt, J = 9.17, 6.60 Hz, 1H), 4.86 (t, J = 1.83 Hz, 1H), 5.86 (t, J = 1.47 Hz,1H), 6.60 (dd, J = 7.70, 1.83 Hz, 1H), 6.65 (s, 1H), 6.71 (d, J = 1.83 Hz, 1H), 7.24−7.28 (m, 2H), 7.30−7.34 (m, 4H), 7.55− 7.62 (m, 4H). 13C NMR (CDCl3, 150 MHz) δ ppm 38.9, 41.7, 44.2, 52.2, 56.0, 80.6, 100.8 107.7, 107.8, 108.1, 120.3, 125.8, 127.1, 127.5, 127.9, 128.3, 128.3, 128.4, 139.4, 139.5, 144.7, 145.7, 147.5. Anal. calcd for C26H24N2O2 C, 78.76; H, 6.10; N, 7.07; Found C, 78.84; H, 6.17; N, 7.16. Yield: 98% (388 mg).

Figure 7. MCF-7 (breast cancer cell line) cells stained with compound HImP 4e (10 μM). (A) and (B) Results from live cells, whereas (C) and (D) are from fixed cells. It was observed an accumulation of this probe (arrows) near to the cells’ nuclei (N). No fluorescence signal was observed inside the nucleus (N). (B) and (D) Cells’ normal morphological aspects by phase contrast image. Reference scale bar 25 μm. 96.1, 100.6, 107.6, 108.0, 115.8, 119.2, 120.1, 122.4, 124.8, 125.0, 127.6, 128.9, 132.2, 135.0, 139.0, 140.1, 145.0, 145.3, 146.8, 152.5, 158.7, 170.6, 170.6. Anal. calcd for C32H24N2O6 C, 72.17; H, 4.54; N, 5.26; Found C, 72.03; H, 4.42; N, 5.11. Yield: 98% (521 mg). 3,3′-((7R,8aS)-7-(4-Hydroxyphenyl)-1-(naphthalen-2-yl)1,2,3,7,8,8a-hexahydroimidazo [1,2-a]pyridine-5,8a-diyl)bis(2H-chromen-2-one) (HImP 4d). Light orange solid, decomposition at 210 °C. 1H NMR (DMSO-d6, 600 MHz) δ ppm 1.18 (t, J = 7.91 Hz, 1H), 1.99 (s, 1H), 2.09 (s, 4H), 6.89 (d, J = 7.33 Hz, 2H), 7.15−7.30 (m, 6H), 7.42−7.51 (m, 4H), 7.66 (d, J = 6.45 Hz, 3H), 7.73−7.79 (m, 3H), 7.96 (d, J = 7.62 Hz, 2 H), 8.69 (s, 2H), 9.73 (s, 2H). 13C NMR (DMSO-d6,150 MHz) δ ppm 14.0, 18.5, 20.7, 30.6, 56.0, 59.7, 114.4, 116.1, 118.1, 120.0, 124.4, 124.9, 130.0, 130.4, 134.2, 135.6, 144.2, 147.0, 154.4, 157.7, 158.4, 187.0. Anal. calcd for C41H30N2O5 C, 78.08; H, 4.79; N, 4.44; Found C, 78.21; H, 4.90; N, 4.59. Yield: 64% (404 mg). 3,3′-((7R,8aS)-7-Phenyl-1,2,3,7,8,8a-hexahydroimidazo[1,2a]pyridine-5,8a-diyl)bis(2H-chromen-2-one) (HImP 4e). White solid, mp 156−158 °C. 1H NMR (CDCl3, 600 MHz) δ ppm 7.36 (dt, J = 7.34, 1.10 Hz, 2H), 7.40−7.43 (m, 7H), 7.65−7.70 (m, 7H), 7.92 (dd, J = 45.12, 15.77 Hz, 4H), 8.60 (s, 2H). 13C NMR (CDCl3, 150 MHz) δ ppm 18.4, 58.4, 116.7, 118.5. 118.6, 123.9(8), 122.9(9), 125.0, 125.3(3), 125.3(5), 128.9(3),128.9 (7), 130.0, 130.8, 134.2, 134.8, 145.1, 148.1, 155.3, 159.3, 186.5. Anal. calcd for C31H24N2O4 C, 76.21; H, 4.95; N, 5.73; Found C, 76.34; H, 5.10; N, 5.84. Yield: 80% (391 mg). ( 7R , 8a S) - 7 - ( 3 , 5 - D i m e t h o x y p h e ny l) - 5 , 8 a - d i p h e n y l 1,2,3,7,8,8a-hexahydroimidazo[1,2-a]pyridine (HImP 4f). Yellow solid, mp 116−118 °C. 1H NMR (CDCl3, 600 MHz) δ ppm 1,69 (t, J = 12.10 Hz, 1H), 2.58 (ddd, J = 12.16, 5.42, 1.03 Hz, 1H), 2.90− 2.97 (m, 1H), 3.03-3,16 (m, 2H), 3.32 (ddd, J = 11.87, 5.27, 2.05 Hz, 1H), 3.58 (dt, J = 8.90, 6.50, 6.50 Hz, 1H), 3.67 (s, 3H), 3,77 (s, 3H), 4,99 (s, 1H), 6.41 (d, J = 2.5 Hz, 1H), 6.47 (dd, J = 8.4, 2.5 Hz, 1H), 7,29−7,41 (m, 7H), 7,67−7,71 (m, 4H). 13C NMR (CDCl3, 150 MHz) δ ppm 31.8; 38.4; 44.2; 52.2; 55.3; 55.3; 80.7; 98.4; 98.4; 103.9; 108.1; 108.2; 125.9; 128.2; 139.9; 144.8; 145.4; 158.1; 159.1. Anal. calcd for C27H28N2O2 C, 78.61; H, 6.84; N, 6.79; Found C, 78.49; H, 6.70; N, 6.68. Yield: 70% (289 mg).

■

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.8b00472. Catalyst analyses, ESI-MS/MS and NMR spectra related with this manuscript (PDF) (CIF)

■

AUTHOR INFORMATION

Corresponding Author

*Phone: (+) 55 61 31073867. E-mail: [email protected]. ORCID

Marcelo O. Rodrigues: 0000-0003-0684-3618 Brenno A. D. Neto: 0000-0003-3783-9283 Notes

The authors declare no competing financial interest. 4051


Article


■

(20) Al-Tel, T. H.; Semreen, M. H.; Al-Qawasmeh, R. A.; Schmidt, M. F.; El-Awadi, R.; Ardah, M.; Zaarour, R.; Rao, S. N.; El-Agnaf, O. Design, Synthesis, and Qualitative Structure-Activity Evaluations of Novel beta-Secretase Inhibitors as Potential Alzheimer’s Drug Leads. J. Med. Chem. 2011, 54, 8373−8385. (21) Wu, Z. C.; Fraley, M. E.; Bilodeau, M. T.; Kaufman, M. L.; Tasber, E. S.; Balitza, A. E.; Hartman, G. D.; Coll, K. E.; Rickert, K.; Shipman, J.; Shi, B.; Sepp-Lorenzino, L.; Thomas, K. A. Design and synthesis of 3,7-diarylimidazopyridines as inhibitors of the VEGFreceptor KDR. Bioorg. Med. Chem. Lett. 2004, 14, 909−912. (22) Turkmen, H.; Ceyhan, N.; Yavasoglu, N. U. K.; Ozdemir, G.; Cetinkaya, B. Synthesis and antimicrobial activities of hexahydroimidazo 1,5-a pyridinium bromides with varying benzyl substituents. Eur. J. Med. Chem. 2011, 46, 2895−2900. (23) Xiao, H.-Y.; Wu, D.-R.; Malley, M. F.; Gougoutas, J. Z.; Habte, S. F.; Cunningham, M. D.; Somerville, J. E.; Dodd, J. H.; Barrish, J. C.; Nadler, S. G.; Dhar, T. G. M. Novel Synthesis of the Hexahydroimidazo 1,5b isoquinoline Scaffold: Application to the Synthesis of Glucocorticoid Receptor Modulators. J. Med. Chem. 2010, 53, 1270−1280. (24) Shao, X.; Zhang, W.; Peng, Y.; Li, Z.; Tian, Z.; Qian, X. cisNitromethylene neonicotinoids as new nicotinic family: Synthesis, structural diversity, and insecticidal evaluation of hexahydroimidazo 1,2-alpha pyridine. Bioorg. Med. Chem. Lett. 2008, 18, 6513−6516. (25) Wu, B.; Santra, M.; Yoshikai, N. A Highly Modular One-Pot Multicomponent Approach to Functionalized Benzo b phosphole Derivatives. Angew. Chem., Int. Ed. 2014, 53, 7543−7546. (26) Moni, L.; Denissen, M.; Valentini, G.; Mueller, T. J. J.; Riva, R. Diversity-Oriented Synthesis of Intensively Blue Emissive 3-Hydroxyisoquinolines by Sequential Ugi Four-Component Reaction/Reductive Heck Cyclization. Chem. - Eur. J. 2015, 21, 753−762. (27) Li, Y.; Liu, Y.-Y.; Chen, X.-J.; Xiong, X.-H.; Li, F.-S. Synthesis, Spectroscopic Characterization, X-Ray Structure, and DFT Calculations of Some New 1,4-Dihydro-2,6-Dimethyl-3,5-Pyridinedicarboxamides. PLoS One 2014, 9, e91361. (28) Levi, L.; Mueller, T. J. J. Multicomponent syntheses of functional chromophores. Chem. Soc. Rev. 2016, 45, 2825−2846. (29) Brauch, S.; Henze, M.; Osswald, B.; Naumann, K.; Wessjohann, L. A.; van Berkel, S. S.; Westermann, B. Fast and efficient MCR-based synthesis of clickable rhodamine tags for protein profiling. Org. Biomol. Chem. 2012, 10, 958−965. (30) de Moliner, F.; Kielland, N.; Lavilla, R.; Vendrell, M. Modern Synthetic Avenues for the Preparation of Functional Fluorophores. Angew. Chem., Int. Ed. 2017, 56, 3758−3769. (31) Sueki, S.; Takei, R.; Zaitsu, Y.; Abe, J.; Fukuda, A.; Seto, K.; Furukawa, Y.; Shimizu, I. Synthesis of 1,4-Dihydropyridines and Their Fluorescence Properties. Eur. J. Org. Chem. 2014, 2014, 5281−5301. (32) Affeldt, R. F.; de Amorim Borges, A. C.; Russowsky, D.; Rodembusch, F. S. Synthesis and fluorescence properties of benzoxazole-1,4-dihydropyridine dyads achieved by a multicomponent reaction. New J. Chem. 2014, 38, 4607−4614. (33) Pina, J.; Pinheiro, D.; Nascimento, B.; Pineiro, M.; Sergio Seixas de Melo, J. The effect of polyaromatic hydrocarbons on the spectral and photophysical properties of diaryl-pyrrole derivatives: an experimental and theoretical study. Phys. Chem. Chem. Phys. 2014, 16, 18319−18326. (34) Soumya, T. V.; Thasnim, P.; Bahulayan, D. Step-economic and cost effective synthesis of coumarin based blue emitting fluorescent dyes. Tetrahedron Lett. 2014, 55, 4643−4647. (35) Saluja, P.; Chaudhary, A.; Khurana, J. M. Synthesis of novel fluorescent benzo[α]pyrano[2,3-c]phenazine and benzo[a]chromeno[2,3-c]phenazine derivatives via facile four-component domino protocol. Tetrahedron Lett. 2014, 55, 3431−3435. (36) Agrebi, A.; Allouche, F.; Chabchoub, F.; El-Kaim, L.; Alves, S.; Baleizao, C.; Farinha, J. P. Sc(OTf)(3) promoted multicomponent synthesis of fluorescent imidazo 1,2-c pyrazolo 3,4-d pyrimidine. Tetrahedron Lett. 2013, 54, 4781−4784.

ACKNOWLEDGMENTS This work has been supported by CAPES, CNPq, FINEPMCT, FINATEC, FAPESP, FAPDF, and DPP-UnB. BAD Neto also thanks INCT-Transcend group and LNLS.

■

REFERENCES

(1) Domling, A.; Wang, W.; Wang, K. Chemistry and Biology Of Multicomponent Reactions. Chem. Rev. 2012, 112, 3083−3135. (2) Gu, Y. L. Multicomponent reactions in unconventional solvents: state of the art. Green Chem. 2012, 14, 2091−2128. (3) Goncalves, I. L.; de Azambuja, G. O.; Kawano, D. F.; Eifler-Lima, V. L. Thioureas as Building Blocks for the Generation of Heterocycles and Compounds with Pharmacological Activity: An Overview. MiniRev. Org. Chem. 2018, 15, 28−35. (4) Wan, J. P.; Gan, L.; Liu, Y. Y. Transition metal-catalyzed C-H bond functionalization in multicomponent reactions: a tool toward molecular diversity. Org. Biomol. Chem. 2017, 15, 9031−9043. (5) Bagdi, A. K.; Santra, S.; Monir, K.; Hajra, A. Synthesis of imidazo[1,2-a]pyridines: a decade update. Chem. Commun. 2015, 51, 1555−1575. (6) Cioc, R. C.; Ruijter, E.; Orru, R. V. A. Multicomponent reactions: advanced tools for sustainable organic synthesis. Green Chem. 2014, 16, 2958−2975. (7) Toure, B. B.; Hall, D. G. Natural Product Synthesis Using Multicomponent Reaction Strategies. Chem. Rev. 2009, 109, 4439− 4486. (8) Khan, M. M.; Khan, S.; Saigal; Iqbal, S. Recent developments in multicomponent synthesis of structurally diversified tetrahydropyridines. RSC Adv. 2016, 6, 42045−42061. (9) Khan, M. M.; Yousuf, R.; Khan, S. Shafiullah. Recent advances in multicomponent reactions involving carbohydrates. RSC Adv. 2015, 5, 57883−57905. (10) Wan, J.-P.; Liu, Y. Recent advances in new multicomponent synthesis of structurally diversified 1,4-dihydropyridines. RSC Adv. 2012, 2, 9763−9777. (11) El Kaim, L.; Grimaud, L. The Ugi-Smiles and Passerini-Smiles Couplings: A Story About Phenols in Isocyanide-Based Multicomponent Reactions. Eur. J. Org. Chem. 2014, 2014, 7749−7762. (12) Estevez, V.; Villacampa, M.; Menendez, J. C. Recent advances in the synthesis of pyrroles by multicomponent reactions. Chem. Soc. Rev. 2014, 43, 4633−4657. (13) Brauch, S.; van Berkel, S. S.; Westermann, B. Higher-order multicomponent reactions: beyond four reactants. Chem. Soc. Rev. 2013, 42, 4948−4962. (14) Banfi, L.; Basso, A.; Moni, L.; Riva, R. The Alternative Route to Enantiopure Multicomponent Reaction Products: Biocatalytic or Organocatalytic Enantioselective Production of Inputs for Multicomponent Reactions. Eur. J. Org. Chem. 2014, 2014, 2005−2015. (15) Jose Climent, M.; Corma, A.; Iborra, S. Homogeneous and heterogeneous catalysts for multicomponent reactions. RSC Adv. 2012, 2, 16−58. (16) Rotstein, B. H.; Zaretsky, S.; Rai, V.; Yudin, A. K. Small Heterocycles in Multicomponent Reactions. Chem. Rev. 2014, 114, 8323−8359. (17) Mahfoudh, M.; Abderrahim, R.; Leclerc, E.; Campagne, J. M. Recent Approaches to the Synthesis of Pyrimidine Derivatives. Eur. J. Org. Chem. 2017, 2017, 2856−2865. (18) Wang, R. L.; Zhu, P.; Lu, Y.; Huang, F. P.; Hui, X. P. Bronsted Acid-Catalyzed Four-Component Cascade Reaction: Facile Synthesis of Hexahydroimidazo 1,2-a pyridines. Adv. Synth. Catal. 2013, 355, 87−92. (19) Kamal, A.; Reddy, V. S.; Karnewar, S.; Chourasiya, S. S.; Shaik, A. B.; Kumar, G. B.; Kishor, C.; Reddy, M. K.; Rao, M. P. N.; Nagabhushana, A.; Ramakrishna, K. V. S.; Addlagatta, A.; Kotamraju, S. Synthesis and Biological Evaluation of Imidazopyridine-Oxindole Conjugates as Microtubule-Targeting Agents. ChemMedChem 2013, 8, 2015−2025. 4052


Article

The Journal of Organic Chemistry (37) Zhao, L.; Chu, Y.; He, C.; Duan, C. Fluorescent detection of RDX within DHPA-containing metal-organic polyhedra. Chem. Commun. 2014, 50, 3467−3469. (38) Zhu, Q.; Huang, L.; Su, J.; Liu, S. A sensitive and visible fluorescence-turn-on probe for the CMC determination of ionic surfactants. Chem. Commun. 2014, 50, 1107−1109. (39) Singh, A.; Raj, T.; Aree, T.; Singh, N. Fluorescent Organic Nanoparticles of Biginelli-Based Molecules: Recognition of Hg2+ and Cl− in an Aqueous Medium. Inorg. Chem. 2013, 52, 13830−13832. (40) Kaur, A.; Sharma, H.; Kaur, S.; Singh, N.; Kaur, N. A counterion displacement assay with a Biginelli product: A ratiometric sensor for Hg2+ and the resultant complex as a sensor for Cl. RSC Adv. 2013, 3, 6160−6166. (41) Homraruen, D.; Sirijindalert, T.; Dubas, L.; Sukwattanasinitt, M.; Ajavakom, A. Selective fluorescent sensor for mercury ions in aqueous media using a 1,4-dihydropyridine derivative. Tetrahedron 2013, 69, 1617−1621. (42) Koner, R. R.; Sinha, S.; Kumar, S.; Nandi, C. K.; Ghosh, S. 2Aminopyridine derivative as fluorescence ’On-Off’ molecular switch for selective detection of Fe3+/Hg2+. Tetrahedron Lett. 2012, 53, 2302−2307. (43) de Souza, V. P.; Vendrusculo, V.; Moras, A. M.; Steffens, L.; Santos, F. S.; Moura, D. J.; Rodembusch, F. S.; Russowsky, D. Synthesis and photophysical study of new fluorescent proton transfer dihydropyrimidinone hybrids as potential candidates for molecular probes. New J. Chem. 2017, 41, 15305−15311. (44) Ramirez-Ornelas, D. E.; Alvarado-Martinez, E.; Banuelos, J.; Lopez Arbeloa, I.; Arbeloa, T.; Mora-Montes, H. M.; Perez-Garcia, L. A.; Pena-Cabrera, E. FormylBODIPYs: Privileged Building Blocks for Multicomponent Reactions. The Case of the Passerini Reaction. J. Org. Chem. 2016, 81, 2888−2898. (45) Passos, S. T. A.; Correa, J. R.; Soares, S. L. M.; da Silva, W. A.; Neto, B. A. D. Fluorescent Peptoids as Selective Live Cell Imaging Probes. J. Org. Chem. 2016, 81, 2646−2651. (46) Vazquez-Romero, A.; Kielland, N.; Arevalo, M. J.; Preciado, S.; Mellanby, R. J.; Feng, Y.; Lavilla, R.; Vendrell, M. Multicomponent Reactions for de Novo Synthesis of BODIPY Probes: In Vivo Imaging of Phagocytic Macrophages. J. Am. Chem. Soc. 2013, 135, 16018− 16021. (47) Medeiros, G. A.; da Silva, W. A.; Bataglion, G. A.; Ferreira, D. A. C.; de Oliveira, H. C. B.; Eberlin, M. N.; Neto, B. A. D. Probing the Mechanism of the Ugi Four-Component Reaction with ChargeTagged Reagents by ESI-MS(/MS). Chem. Commun. 2014, 50, 338− 340. (48) Alvim, H. G. O.; Lima, T. B.; de Oliveira, A. L.; de Oliveira, H. C. B.; Silva, F. M.; Gozzo, F. C.; Souza, R. Y.; da Silva, W. A.; Neto, B. A. D. Facts, Presumptions, and Myths on the Solvent-Free and Catalyst-Free Biginelli Reaction. What is Catalysis for? J. Org. Chem. 2014, 79, 3383−3397. (49) Alvim, H. G. O.; de Lima, T. B.; de Oliveira, H. C. B.; Gozzo, F. C.; de Macedo, J. L.; Abdelnur, P. V.; Silva, W. A.; Neto, B. A. D. Ionic Liquid Effect over the Biginelli Reaction under Homogeneous and Heterogeneous Catalysis. ACS Catal. 2013, 3, 1420−1430. (50) Carvalho, P. H. P. R.; Correa, J. R.; Guido, B. C.; Gatto, C. C.; De Oliveira, H. C. B.; Soares, T. A.; Neto, B. A. D. Designed Benzothiadiazole Fluorophores for Selective Mitochondrial Imaging and Dynamics. Chem. - Eur. J. 2014, 20, 15360−15374. (51) Diniz, J. R.; Correa, J. R.; Moreira, D. D.; Fontenele, R. S.; de Oliveira, A. L.; Abdelnur, P. V.; Dutra, J. D. L.; Freire, R. O.; Rodrigues, M. O.; Neto, B. A. D. Water-Soluble Tb3+ and Eu3+ Complexes with Ionophilic (Ionically Tagged) Ligands as Fluorescence Imaging Probes. Inorg. Chem. 2013, 52, 10199−10205. (52) Alvim, H. G. O.; Bataglion, G. A.; Ramos, L. M.; de Oliveira, A. L.; de Oliveira, H. C. B.; Eberlin, M. N.; de Macedo, J. L.; da Silva, W. A.; Neto, B. A. D. Task-Specific Ionic Liquid Incorporating Anionic Heteropolyacid-Catalyzed Hantzsch and Mannich Multicomponent Reactions. Ionic Liquid Effect Probed by ESI-MS(/MS). Tetrahedron 2014, 70, 3306−3313.

(53) Rodrigues, T. S.; Silva, V. H. C.; Lalli, P. M.; de Oliveira, H. C. B.; da Silva, W. A.; Coelho, F.; Eberlin, M. N.; Neto, B. A. D. MoritaBaylis-Hillman Reaction: ESI-MS(/MS) Investigation with Charge Tags and Ionic Liquid Effect Origin Revealed by DFT Calculations. J. Org. Chem. 2014, 79, 5239−5248. (54) Pilli, R. A.; Robello, L. G.; Camilo, N. S.; Dupont, J.; Moreira Lapis, A. A.; da Silveira Neto, B. A. Addition of activated olefins to cyclic N-acyliminium ions in ionic liquids. Tetrahedron Lett. 2006, 47, 1669−1672. (55) Stassen, H. K.; Ludwig, R.; Wulf, A.; Dupont, J. Imidazolium salt ion Pairs in solution. Chem. - Eur. J. 2015, 21, 8324−8335. (56) Dupont, J. From Molten Salts to Ionic Liquids: A ″Nano″ Journey. Acc. Chem. Res. 2011, 44, 1223−1231. (57) Dupont, J.; Scholten, J. D. On the structural and surface properties of transition-metal nanoparticles in ionic liquids. Chem. Soc. Rev. 2010, 39, 1780−1804. (58) Dupont, J. On the solid, liquid and solution structural organization of imidazolium ionic liquids. J. Braz. Chem. Soc. 2004, 15, 341−350. (59) Lavis, L. D.; Raines, R. T. Bright Building Blocks for Chemical Biology. ACS Chem. Biol. 2014, 9, 855−866. (60) Lavis, L. D.; Raines, R. T. Bright Ideas for Chemical Biology. ACS Chem. Biol. 2008, 3, 142−155. (61) Johnsson, N.; Johnsson, K. Chemical Tools for Biomolecular Imaging. ACS Chem. Biol. 2007, 2, 31−38. (62) Coelho, F.; Eberlin, M. N. The Bridge Connecting Gas-Phase and Solution Chemistries. Angew. Chem., Int. Ed. 2011, 50, 5261− 5263. (63) Eberlin, M. N. Electrospray ionization mass spectrometry: a major tool to investigate reaction mechanisms in both solution and the gas phase. Eur. J. Mass Spectrom. 2007, 13, 19−28. (64) Dupont, J.; Eberlin, M. N. Structure and Physico-Chemical Properties of Ionic Liquids: What Mass Spectrometry is Telling Us. Curr. Org. Chem. 2013, 17, 257−272. (65) Santos, L. S. Online mechanistic investigations of catalyzed reactions by electrospray ionization mass spectrometry: A tool to intercept transient species in solution. Eur. J. Org. Chem. 2008, 2008, 235−253. (66) Santos, L. S. What do We Know about Reaction Mechanism? The Electrospray Ionization Mass Spectrometry Approach. J. Braz. Chem. Soc. 2011, 22, 1827−1840. (67) Limberger, J.; Leal, B. C.; Monteiro, A. L.; Dupont, J. Chargetagged ligands: useful tools for immobilising complexes and detecting reaction species during catalysis. Chem. Sci. 2015, 6, 77−94. (68) Vikse, K. L.; McIndoe, J. S. Mechanistic insights from mass spectrometry: examination of the elementary steps of catalytic reactions in the gas phase. Pure Appl. Chem. 2015, 87, 361−377. (69) Yunker, L. P. E.; Stoddard, R. L.; McIndoe, J. S. Practical approaches to the ESI-MS analysis of catalytic reactions. J. Mass Spectrom. 2014, 49, 1−8. (70) Chisholm, D. M.; McIndoe, J. S. Charged ligands for catalyst immobilisation and analysis. Dalton Trans. 2008, 3933−3945. (71) Neto, B. A. D.; Lapis, A. A. M.; Bernd, A. B.; Russowsky, D. Studies on the Eschenmoser coupling reaction and insights on its mechanism. Application in the synthesis of Norallosedamine and other alkaloids. Tetrahedron 2009, 65, 2484−2496. (72) Glatz, J. F. C.; Luiken, J. J. F. P.; Bonen, A. Membrane Fatty Acid Transporters as Regulators of Lipid Metabolism: Implications for Metabolic Disease. Physiol. Rev. 2010, 90, 367−417.

4053


Heteropolyacid-Containing Ionic Liquid-Catalyzed Multicomponent

Recommend Documents