Heteropolyacid-Containing Ionic Liquid-Catalyzed Multicomponent

Mar 16, 2018 - The current manuscript describes the use of a heteropolyacid-containing task-specific ionic liquid, supported in imidazolium-based ioni...
1 downloads 6 Views 1MB Size
Subscriber access provided by - Access paid by the | UCSB Libraries

Heteropolyacid-Containing Ionic Liquid-Catalyzed Multicomponent Synthesis of Bridgehead Nitrogen Heterocycles: Mechanisms and Mitochondrial Staining Haline G. O. Alvim, Jose Raimundo Correa, José A. F. Assumpção, Wender Alves da Silva, Marcelo Oliveira Rodrigues, Julio Lemos de Macedo, Mariana Fioramonte, Fabio Cesar Gozzo, Claudia C Gatto, and Brenno A. D. Neto J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00472 • Publication Date (Web): 16 Mar 2018 Downloaded from http://pubs.acs.org on March 16, 2018

Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.

is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

Page 1 of 26 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

The Journal of Organic Chemistry

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

Laboratory of Medicinal and Technological Chemistry, University of Brasília, Chemistry Institute (IQ-UnB), Campus Universitário Darcy Ribeiro, CEP 70904-970 - P.O.Box 4478-Brasília, DF, Brazil. Phone: (+) 55 61 31073867. [email protected]

b

LIMA-Laboratório de Inorgânica e Materiais, Campus Universitário Darcy Ribeiro, CEP 70904970, P.O.Box 4478, Brasilia-DF, Brazil.

c

Laboratory of Catalysis, Institute of Chemistry, University of Brasília (IQ-UnB).

d

Institute of Chemistry, University of Campinas (Unicamp), Campinas, SP, Brazil.

Abstract. The current manuscript describes the use of a heteropolyacid-containing

task-specific

ionic

liquid,

supported in imidazolium-based 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 one hour 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 were synthesized and its fluorescent properties allowed it to be tested as a probe for live cell imaging experiments with a preference for mitochondria. Key words. Catalysis, multicomponent reaction, ionic liquids, hexahydroimidazo[1,2-a]pyridine, ESIMS, mechanism, cell-imaging, heterocycles, mitochondria.

1 ACS Paragon Plus Environment

The Journal of Organic Chemistry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 2 of 26

Introduction The development of multicomponent reactions (MCRs) and their applications for onepot 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 recent been synthesized through a MCR approach.18 Landmark work of Hui and coworkers18 described the syntheses of HImPs using 20 mol% of a Bronsted acid as the promoter, with ketone excess and typically in 24 hours of reaction through a new multicomponent approach (Scheme 1).

2 ACS Paragon Plus Environment

Page 3 of 26 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

The Journal of Organic Chemistry

Scheme 1. Multicomponent approach for the synthesis of hexahydroimidazo[1,2-a]pyridine derivatives (HImPs). Note it is a four-component reaction.

Although 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 but in 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 actions and dynamics in live cells. Their preferred localization inside live cells remains unclear. Recently, it is observed 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. 3 ACS Paragon Plus Environment

The Journal of Organic Chemistry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 4 of 26

An improved catalyzed version of the reaction in imidazolium ionic liquids and its mechanism is evaluated by 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 MCRs,49,52 and catalysis in ionic liquids,53,54 we decided to investigate its use for HImPs syntheses (Scheme 2) under different reaction conditions. Only a few set of techniques was previously employed to characterize the known catalyst MSI3PW. In the supplementary material (see the supporting information file, Figures S1-S3) we have therefore 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.

Scheme 2. Model reaction for the synthesis of HImP 4a catalyzed by the MSI3PW.

The reactions conditions were optimized based on the results described in Table 1.

4 ACS Paragon Plus Environment

Page 5 of 26 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

The Journal of Organic Chemistry

Table 1. Reaction conditions for the synthesis of HImP 4a using benzaldehyde (1.00 mmol), acetophenone (2.00 mmols) and ethylenediamine (1.00 mmol) during a time period of 60 min. The reactions were conducted in sealed Schlenk tubes to avoid solvent loss. Entry Catalyst (mol%) Solvent (1 mL) Temperature (°C) Yield (%)b 1 70 9 2 2 H2O 70 19 3 2 MeOH 70 21 4 2 EtOH 70 11 5 2 MeCN 70 14 6 2 PhMe 70 15 7 2 CH2Cl2 70 15 8 2 THF 70 5 9 2 BMI.PF6 70 12 10 2 BMI.BF4 70 31 11 2 BMI.BF4 40 17 12 2 BMI.BF4 50 19 13 2 BMI.BF4 60 22 14 2 BMI.BF4 70 31 15 2 BMI.BF4 80 32 16 2 BMI.BF4 90 29 17 2 BMI.BF4 100 10 18 1 BMI.BF4 70 23 19 3 BMI.BF4 70 51 20 4 BMI.BF4 70 67 21 5 BMI.BF4 70 91 22 7 BMI.BF4 70 60 23a 20 MeOH 70 90 a Conditions and yield described elsewhere.18 Catalyst: p-toluenesulfonic acid; Excess of acetophenone (2.50 mmol); 12 h of reaction. b Isolated yields.

For all tested conditions no reagent excess was used towards a greener synthesis. BMI.BF4 (1-n-butyl-3-methylimidazolium tetrafluoroborate) 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 points to a positive ionic liquid effect55-58 over the reaction, although it has been described18 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

5 ACS Paragon Plus Environment

The Journal of Organic Chemistry

The reaction profile (yield vs. time) was also evaluated under the optimized condition and results are better visualized in Figure 1. It is depicted 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. 100

80

60

Yield (%)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 6 of 26

40

20

0 0

20

40

60

80

100

120

140

160

180

Time (min)

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

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 (°) for HImP 4a.

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

6 ACS Paragon Plus Environment

Page 7 of 26 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

The Journal of Organic Chemistry

Several HImPs could be therefore synthesized using the optimized reaction conditions and the results are visualized in Table 2. Table 2. HImP derivatives synthesized using the developed conditions (70 °C, 1 mL of BMI.BF4, 60 min, MSI3PW 5 mol%, 1 mmol of the aldehyde, 1 mmol of ethylenediamine and 2 mmols of the ketone). HImP

Aldehyde

Ketone

Product

Yield (%)

91

4a

O 83

4b

O

O

O 98

4c

O

O

O 4da

64

O

O

7 ACS Paragon Plus Environment

The Journal of Organic Chemistry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 8 of 26

O 80

4e

O

O

4f

70

4g

73

4h

70

4i

55

8 ACS Paragon Plus Environment

Page 9 of 26 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

The Journal of Organic Chemistry

98

4j

a

N-2-Naphthyl-ethylenediamine (1 mmol) instead of ethylenediamine.

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, were evaluated by electrospray (tandem) mass spectrometry-ESI-MS(/MS). The polar and cationic nature 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 intermediates65) 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 non-catalyzed reactions.47,48,53,71

9 ACS Paragon Plus Environment

The Journal of Organic Chemistry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 10 of 26

In this context, we have used three different charge-tagged reagents (Figure 3) to probe the mechanism of the catalyzed reaction. We have already reported the MSI3PW characterization by ESI-MS(/MS) elsewhere.49,52

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.

The online

monitoring by ESI(+)-MS(/MS) of the (four-component)

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 mixtures were previously heated (70 °C for 20 minutes) and then analyzed. The results obtained by using the charge-tagged aldehyde are better visualized in Figure 4.

10 ACS Paragon Plus Environment

Page 11 of 26 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

The Journal of Organic Chemistry

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

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).

11 ACS Paragon Plus Environment

The Journal of Organic Chemistry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 12 of 26

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

12 ACS Paragon Plus Environment

Page 13 of 26 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

The Journal of Organic Chemistry

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).

Scheme 3. Catalytic cycle for the formation of hexahydroimidazo[1,2-a]pyridine derivatives under acid catalysis.

13 ACS Paragon Plus Environment

The Journal of Organic Chemistry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 14 of 26

The proposed catalytic cycle is in accordance with the original prediction of Hui and coworkers.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.

14 ACS Paragon Plus Environment

Page 15 of 26 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

The Journal of Organic Chemistry

Scheme 4. Alternative catalytic cycle for the formation of hexahydroimidazo[1,2-a]pyridine derivatives under acid catalysis.

The alternative proposition also explain 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

15 ACS Paragon Plus Environment

The Journal of Organic Chemistry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 16 of 26

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. Table 3. Photophysical data (in different solvents) for 4e (10 µM for all analyses).

Compound

4e

Solvent (Dipolar moment - D) Toluene (0.36) CHCl3 (1.04) CH2Cl2 (1.60) Ethanol (1.69) Methanol (1.70) H2O (1.85) CH3CN (3.92) DMSO (3.96)

λmax(abs) (nm)

Log ε

λmax em (nm)

Stokes shift (nm)

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

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 3.784.26 mM-1 cm-1) are also noted. Small variation is noted at their absorption maxima (∆λ = 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 indicate 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.

16 ACS Paragon Plus Environment

Page 17 of 26 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

The Journal of Organic Chemistry

Figure 7. MCF-7 (breast cancer cell line) cells stained with compound HImP 4e (10 µM). (A) and (B) are the 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) show the cells’ normal morphological aspects by phase contrast image. Reference scale bar 25 µm.

HImP 4e emitted an intense green fluorescence inside breast cancer cells (MCF7). Both live and fixed cells returned similar results. The probe showed an accumulation near to the cells’ 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 a heteropolyacidcontaining task-specific ionic liquid as the catalyst allowed the synthesis of ten 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 17 ACS Paragon Plus Environment

The Journal of Organic Chemistry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 18 of 26

same final adduct could be obtained. The incorporation of coumarin scaffolds in the structure of 4e made the structure prone to be used as live cell imaging probe. The use of the new compound in bioimaging showed the MCR adduct had a preference for mitochondria.

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. 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 minutes 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

13

C. 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 point 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 mmols 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 ºC under stirring for 60 min. The catalyst MSI3PW was then removed by filtration in celite/alumina system and using ethyl acetate as the eluent. The organic solvent was removed and the HImPs were purified by solvent crystallization (ethanol for 4a, e, f, g; water for 4h and acetone for 4i). HImPs

18 ACS Paragon Plus Environment

Page 19 of 26 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

The Journal of Organic Chemistry

4b-d 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, m.p. 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), 7.297.36 (m, 5H), 7.40-7.41 (m, 4H), 7.65-7.71 (m, 4H). 13C 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)-1,2,3,7,8,8a-hexahydroimidazo[1,2a]pyridine-5,8a-diyl)bis(2H-chromen-2-one) (HImP 4b). Red solid, m.p. 214-215 °C. 1

H NMR (DMSO-d6, 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)-1,2,3,7,8,8a-hexahydroimidazo[1,2a]pyridine-5,8a-diyl)bis(2H-chromen-2-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 = 19 ACS Paragon Plus Environment

The Journal of Organic Chemistry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

7.70 Hz, 1H), 8.15 (s, 1H)

13

Page 20 of 26

C NMR (DMSO-d6, 150 MHz) δ ppm 20.9, 34.4, 37.7,

40.2, 42.7, 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)-1,2,3,7,8,8ahexahydroimidazo [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[1,2-a]pyridine-5,8adiyl)bis(2H-chromen-2-one) (HImP 4e). White solid, m.p. 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,8aS)-7-(3,5-dimethoxyphenyl)-5,8a-diphenyl-1,2,3,7,8,8ahexahydroimidazo[1,2-a]pyridine (HImP 4f). Yellow solid, m.p. 116-118 °C. 1H

20 ACS Paragon Plus Environment

Page 21 of 26 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

The Journal of Organic Chemistry

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). 4-((7R,8aS)-5,8a-diphenyl-1,2,3,7,8,8a-hexahydroimidazo[1,2-a]pyridin-7-yl)-N,Ndimethylaniline (HImP 4g). White solid, m.p. 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-1,2,3,7,8,8a-hexahydroimidazo[1,2a]pyridine (HImP 4h). Red solid, m.p. 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,

21 ACS Paragon Plus Environment

The Journal of Organic Chemistry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 22 of 26

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)-2methoxyphenol (HImP 4i). Brown solid, m.p. 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-diphenyl-1,2,3,7,8,8ahexahydroimidazo[1,2-a]pyridine (HImP 4j). White solid, m.p. 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).

22 ACS Paragon Plus Environment

Page 23 of 26 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

The Journal of Organic Chemistry

Acknowledgments This work has been supported by CAPES, CNPq, FINEP-MCT, FINATEC, FAPESP, FAPDF, and DPP-UnB. BAD Neto also thanks INCT-Transcend group and LNLS. Supporting Information Catalyst analyses, ESI-MS/MS and NMR spectra related with this manuscript. These materials are available free of charge via the internet at http://pubs.acs.org. 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. Mini-Rev. 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, 90319043. (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, 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) Climent, M. J.; 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, 2856-2865.

23 ACS Paragon Plus Environment

The Journal of Organic Chemistry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 24 of 26

(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. (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 VEGF-receptor 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. cis-Nitromethylene 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-3,5Pyridinedicarboxamides. 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, 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, 1831918326. (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[2,3c]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. (37) Zhao, L.; Chu, Y.; He, C.; Duan, C. Fluorescent detection of RDX within DHPA-containing metalorganic polyhedra. Chem. Commun. 2014, 50, 3467-3469.

24 ACS Paragon Plus Environment

Page 25 of 26 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

The Journal of Organic Chemistry

(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, 1383013832. (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.; Sukvvattanasinitt, 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. 2-Aminopyridine 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.; MoraMontes, 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, 28882898. (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. Morita-Baylis-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.; Lapis, A. A. M.; Neto, B. A. D. Addition of activated olefins to cyclic N-acyliminium ions in ionic liquids. Tetrahedron Lett. 2006, 47, 16691672. (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, 12231231. (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.

25 ACS Paragon Plus Environment

The Journal of Organic Chemistry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 26 of 26

(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, 235253. (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. Charge-tagged 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.

26 ACS Paragon Plus Environment