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Article

Efficient Synthesis of Core-Fluorinated BODIPY-3,5-Diamides

by
Victoria E. Shambalova
1,
Sofiya R. Mikheeva
1,
Alexander S. Aldoshin
1,
Anna A. Moiseeva
1,
Evgeniya A. Safonova
2,
Yulia G. Gorbunova
2,3 and
Valentine G. Nenajdenko
1,*
1
Department of Chemistry, M. V. Lomonosov Moscow State University, Leninskie Gory 1, Building 3, Moscow 119991, Russia
2
Frumkin Institute of Physical Chemistry and Electrochemistry, Russian Academy of Sciences, Leninsky pr., 31, Building 4, Moscow 119071, Russia
3
Kurnakov Institute of General and Inorganic Chemistry, Russian Academy of Sciences, Leninsky pr., 31, Moscow 119991, Russia
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2025, 26(10), 4484; https://doi.org/10.3390/ijms26104484
Submission received: 11 April 2025 / Revised: 3 May 2025 / Accepted: 5 May 2025 / Published: 8 May 2025
(This article belongs to the Special Issue Heterocyclic Compounds: Synthesis, Design, and Biological Activity)
Browse Figures
Versions Notes

Abstract

A modular synthesis of a new family of core-fluorinated BODIPYs was elaborated. β-Fluoro-β-nitrostyrenes were used as starting materials to prepare a set of mono-fluorinated pyrrole-2-amides using the Barton-Zard reaction with 2-isocyanoacetamides. The prepared monofluorinated building blocks were successively transformed into the corresponding dipyrromethanes and 1,7-difluoro-BODIPY-3,5-diamides. As a result, a new family of luminophores with a combination of fluorescence and photosensitizing properties was obtained. The photophysical properties of novel BODIPYs were studied by UV-vis and fluorescence spectroscopy, cyclic voltammetry and DFT calculations. In addition, their ability to generate singlet oxygen was assessed. The properties of 1,7-difluoro-BODIPY-3,5-diamides were compared with their analogues to reveal the substituent effect at the 3,5-positions. The fluorescent properties of the obtained dyes were significantly improved in comparison to their 3,5-diester analogous.

1. Introduction

Boron-dipyrromethenes (BODIPYs) are an important class of pyrrole-derived organic dyes [1,2,3,4]. The properties of BODIPYs are strictly related to their structure. Therefore, structural modification of BODIPY cores has been studied for tuning their photophysical and electrochemical properties for different applications [5,6,7,8,9,10]. As a result, this class of dyes has found a wide application as fluorescent markers for bioimaging [11,12], agents for photoacoustic imaging [13], fluorescent sensors [14,15], triplet photosensitizers for photodynamic therapy, photoredox catalysis [16,17,18,19,20] and solar energy conversion [21], in materials for optoelectronic devices [22], electro- and chemiluminescence [23], drug delivery [24], etc.
On the other hand, the introduction of fluorine into organic chromophores is a very powerful tool that can allow their significant improvement in different applications. Indeed, fluorination of dyes affects their electronic and structural properties and as a consequence their photophysical characteristics [25]. In addition, the replacement of potentially oxidizable C-H bonds with stronger C-F bonds can increase the chemical and photostability of fluorinated dyes. Indeed, fluorination of some classical dyes has improved their properties [26]. For example, enhanced photostability and lower pKa have been observed for fluorinated fluorescein, known as Oregon green, compared to the parent fluorescein [27,28]. Fluorinated derivatives of Rhodamine dyes have demonstrated enhanced resistance to photobleaching [29]. In turn, significant improvements in power output and photostability have been achieved for classical laser dyes even by non-selective electrophilic fluorination [30].
However, the preparation of core-fluorinated BODIPYs is not a trivial task. This is because late-stage fluorination of the BODIPY core is very challenging. Indeed, to our best knowledge, only three compounds of this type have been reported by electrophilic fluorination of the BODIPY core with Selectfluor [31]. The described approach was limited to introducing only one fluorine into the structure in a very low yield. Nevertheless, fluorination at the 2-position has considerably enhanced the photostability of BODIPY.
Recently we have initiated a new project aimed at the preparation of core-fluorinated BODIPYs via an alternative approach using fluorinated building blocks. Such a very convenient constructive approach would allow us to install fluorine atoms at the strictly specified position of the dyes. As a result, β-fluoro-β-nitrostyrenes [32,33] were found to be suitable building blocks for constructing 3-aryl-4-fluoro-1H-pyrrole-2-carboxylates [34], which were subsequently converted into two families of novel 1,7-difluorinated BODIPYs (Figure 1) [35,36,37]. However, diester-derived BODIPYs exhibited poor fluorescent properties.
We supposed that the replacement of ethoxycarbonyl groups with more rotationally restricted amide ones could improve the fluorescence properties of this type of dye (Figure 1). The corresponding rotational barrier for the ester group is considerably lower than the amide one [38,39]. Indeed, BODIPY-2,6- [40,41,42] and 3,5-diamides [43] have demonstrated much better fluorescence properties and have been studied as fluorescent probes for imaging living cells and detection of hypochlorous acid [44,45] and peroxynitrite anion [46].
This work is devoted to the modular synthesis of a new family of 1,7-difluoro-BODIPY-3,5-diamide from β-fluoro-β-nitrostyrene and the study of their photophysical properties.

2. Results and Discussion

2.1. Synthesis

First, the Barton-Zard reaction of β-fluoro-β-nitrostyrene 1 with 2-isocyanoacetamides [47] was studied to prepare the corresponding monofluorinated pyrroles 2 (Scheme 1). We have found previously that the key step of this approach is aromatization to form the corresponding pyrrole via the elimination of either HF (pKa 3.17) or nitrous acid (pKa 3.4) [34]. As a result, we expected the formation of the target 4-fluoropyrroles 2 and the corresponding 4-nitropyrroles 3 as a side reaction product. It was found that the Barton-Zard reaction of β-fluoro-β-nitrostyrene 1 with 2-isocyanoacetamides afforded the desired pyrroles 2 in low to moderate yield (17–53%). As expected, less acidic 2-isocyanoacetamides proved to be less effective in terms of selectivity and product yield compared to the previously studied reaction of ethyl 2-isocyanoacetate [34]. Nevertheless, a set of pyrrole-amides 2 was prepared with up to 53% yield. In all cases, the corresponding nitro derivatives 3 were minor products easily separated from the target fluorinated pyrroles 2 by column chromatography.
Next, the synthesis of dipyrromethanes was studied. For this aim, these novel fluorinated blocks 2 were involved in the condensation with 2,4,5-trimethylbenzaldehyde in the presence of triflic acid (Scheme 2). As a result, a number of dipyrromethanes 4 were prepared in up to 100% yield. Dipyrromethanes 4 were subjected to the subsequent oxidation with DDQ followed by complexation with BF3∙Et2O. Both steps were activated by microwave irradiation at a constant temperature of 60 °C. Thus, a series of novel core-fluorinated BODIPY-3,5-diamides 5a–5e with diverse amide moiety was obtained in up to 90% yield.
It is known that free rotation of a phenyl ring at the meso-position causes fluorescence quenching [48,49]. Rotationally restricted aryl substituents are favourable for fluorescence properties [50,51]. Therefore, modular synthesis of BODIPY 5g–5j based on pyrrole 2e involving other ortho-substituted aromatic aldehydes was carried out. BODIPY 5f with phenyl ring at meso-position was also prepared to assess of meso-substituent effect for this structural type of BODIPY (Scheme 3).
We found that morpholine-derived pyrrole 2e efficiently reacted with any aromatic aldehydes. Both sterically hindered and highly electron-rich aldehydes gave the corresponding dipyrromethanes 4 in quantitative yields. The subsequent oxidation and complexation afforded a series of novel core-fluorinated BODIPY-3,5-diamides 5f–5j with diverse meso-aryl moiety in up to 88% yield. The structures of all novel intermediates and dyes were confirmed by a combination of 1H, 13C and 19F NMR spectroscopy and high-resolution mass-spectroscopy.

2.2. Photophysical Properties

Next, the photophysical properties of obtained luminophores 5 were studied. First, UV–vis absorption and fluorescence spectra were measured for BODIPY 5a in different solvents to investigate solvatofluorochromism (Table 1, See Supplementary Materials, Figure S1).
It was found that the position of the absorption and emission maxima changes depending on the nature of the solvent. The largest bathochromic (18 nm) and bathofloral shifts (13 nm) were observed in nonpolar toluene compared to polar methanol. In addition, it was noted that fewer polar solvents are favourable for fluorescent properties (Table 1, Cf. entries 1–3 and 4–7). Thus, the best result, ΦF = 0.16, was achieved in THF (Table 1, entry 3).
Next, UV–vis absorption and fluorescence spectra were measured for all BODIPY 5 in THF (Figure 2, Table 2). These spectra were found to be very similar for all BODIPYs 5 (See Supplementary Materials, Tables S1–S9, Figures S2–S10). For example, the absorption maximum for the main intense band varies in a narrow range of 531–545 nm. The emission maximum of BODIPYs 5a–h varies in the range of 577–597 nm. Their Stokes shifts change from 42 nm to 52 nm. The variation of the structure of an amide group did not affect the absorption and emission maxima (Table 2, entries 1–5). In turn, the change of an aryl substituent at the meso-position has a noticeable effect only in the case of 2,4-dichlorophenyl group (5h). A red shift was observed for both absorption (12 nm) and emission maxima (13 nm) compared to meso-phenyl-substituted BODIPY 5f (Table 2, Cf. entries 6 and 8).
The quantum yield of fluorescence for 5f is expectedly low (ΦF = 0.01) due to the free rotation of the phenyl group (Table 2, entry 6). However, the replacement of phenyl with rotationally restricted 2-methylphenyl group led to a significant increase of ΦF from 0.01 to 0.16 (Table 2, Cf. entries 6 and 7). The change of the 2-methylphenyl group with 2,4,5-tri methylphenyl group gave somewhat lower ΦΔ for BODIPY 5e (Table 2, entry 5). BODIPYs 5a–5d with primary amide groups demonstrated similar values of ΦF (0.09–0.17) compared to those of morpholine-substituted dyes 5e, 5g (0.12–0.16).
The usage of other rotationally restricted meso-aryls was found ineffective. For example, BODIPY 5h having two chlorines at 2,4-positions of the phenyl ring showed ΦF of 0.03 (Table 2, entry 8). In turn, the replacement of methyl groups with strong electron-donating methoxy ones completely quenches fluorescents in dyes 5i–5j (Table 2, Cf. entries 5, 7 with 9, 10).
It is also known that meso-aryl moiety can be used as a donor subunit, while a BODIPY core is an acceptor subunit, for the creation of donor-acceptor dyad. The dihedral angle between donor and acceptor subunits close to 90 °C is favourable for the realization of a spin-orbit charge transfer intersystem crossing (SOCT-ISC) [52]. Therefore, the usage of rotationally restricted meso-aryl is also favourable for singlet oxygen generation.
The ability of BODIPY 5 to generate singlet oxygen was measured in acetonitrile (Table 2). We found that photosensitizing and fluorescence properties for studied BODIPY demonstrated a very similar trend. Indeed, BODIPYs 5i–5j with highly electron-rich methoxy-substituted phenyl rings did not show any singlet oxygen generation (Table 2, entries 9–10). In turn, meso-phenyl substituted BODIPY 5f showed a very low singlet oxygen quantum yield (ΦΔ) of <0.05. For the other dyes, ΦΔ was found in a range of 0.09–0.16.

2.3. Comparison of Structurally Related Core-Fluorinated BODIPYs

Next, the photophysical properties of obtained BODIPY-diamides were compared with structurally related core-fluorinated BODIPYs [35,36,37] to reveal the substituent effect at the 3,5-positions (Table 3). As one can see, the replacement of amide groups with methyl ones leads to a blue shift of both absorption and emission maxima (See Supplementary Materials, Table S11, Figure S12). In turn, the change of amide groups with ethoxycarbonyl ones results in a slight hypsochromic shift of λabs (max) and bathofloral shift of λem (max) (See Supplementary Materials, Table S10, Figure S11). Methyl groups provide a narrower Stokes shift (35 nm), whereas ethoxycarbonyl groups provide a broader shift (56 nm) than amide groups at the 3,5-positions (44–46 nm). However, the substituents at 3,5-position have the most significant effect on fluorescent properties. While the diester derivative 5k exhibits virtually no fluorescent properties, the diamide derivatives 5a and 5e exhibit moderate fluorescent properties, and the dimethyl derivative 5l exhibits excellent fluorescent properties. The electronic effect of 3,5-substituents on singlet oxygen generation is negligible. Indeed, BODIPY with both electron-donating (EDG) 5l and electron-withdrawing groups (EWG) 5e and 5k demonstrated similar values of ΦΔ.
Next, the cyclic voltammetry (CV) and rotating disk electrode (RDE) methods were performed to study the influence of 3,5-substituents of BODIPY 5a, 5e, 5k and 5l on their electrochemical properties. Measurements were performed on a cleaned surface of a glassy carbon (GC) electrode in acetonitrile solutions. Voltamperograms were recorded from 0 to the cathodic or anodic potential region (Figure 3). The values of half-peak potential are summarized in Table 4. The studied BODIPYs were reduced in two one-electron stages, the first of which was reversible. Oxidation is irreversible and more than one electron is accompanied by adsorption, as evidenced by the observed current drop in the RDE experiments (See Supplementary Materials, Figure S13).
The change in cathodic potentials turned out to be more significant (change range of 500 mV) compared to anodic potentials (change range of 340 mV) depending on the nature of 3,5-substituents (Figure 3, Table 4). It was found that the value of the potentials depends on the electronic effect of the substituents. As expected, both the cathodic and anodic potentials gradually decrease with the diminution of the electron-withdrawing capacity of 3,5-substituents in a row: 5k > 5a > 5e > 5l.
Finally, DFT calculations were performed to compare the electronic structure of BODIPYs 5a, 5e, 5k and 5l [53]. The optimized geometry of the ground electronic state of compounds 5e, 5k and 5l, the frontier orbitals localization and electrostatic potential maps (EPM) are depicted in Figure 4.
Frontier orbital localization is very similar for all structures. Both the highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO) are localized on the BODIPY core and on the 3,5-substituents. LUMO to some extent localized on a phenyl ring at the meso-position, whereas HOMO is not localized (Figure 4). LUMO is localized on the 1,7-fluorines, but HOMO is not localized, except for 5l where slight localization of HOMO is observed.
EPMs of BODIPYs 5e, 5k and 5l visualize charge distributions for these molecules (Figure 4). The nature of the substituents at the 3,5 positions makes a significant contribution to the charge distribution. For dyes 5k, 5e the most electronegative sites (coloured in red) are mainly located around the -BF2, pyrrole nitrogens, electron-withdrawing carbonyl groups and phenyls at the 2,6-positions. The replacement of EWG groups with electron-donating methyl ones (5l) significantly reduces electronegative charge around the 1,7-positions and on neighbouring phenyl rings. On the other hand, less negative sites (coloured in blue) are mainly located around the phenyl at the meso-position. This charge distribution is favourable for the implementation of SOCT-ISC, which is confirmed by experimental data on the generation of singlet oxygen.
In addition, the energies of HOMO, LUMO and the energy gap between them (Egap) were calculated (Figure 5).
Electron-withdrawing morpholine-amide and ethoxycarbonyl groups have a similar impact on the level of the frontier orbitals. In turn, n-butylamide groups lead to a decrease in both frontier orbitals. In contrast, electron-donating methyl groups increase the energy of both HOMO and LUMO compared to EWG-containing BODIPYs 5a, 5e, and 5k. In both cases, the change of LUMO is more significant than HOMO, resulting in compression of Egap for 5a and extension of Egap for 5l.

3. Materials and Methods

3.1. Materials

Synthesis of the starting 2-isocyanoacetamides was carried out according to the described procedures and all of them are known compounds [54,55]. Diethyl 5,5′-((2,4,5-trimethylphenyl)methylene)bis(4-fluoro-3-phenyl-1H-pyrrole-2-carboxylate) and BODIPY 5l were previously obtained and characterized [37]. All other reagents were purchased from commercial sources and used as received (Sigma-Aldrich, St. Louis, MO, USA; Macklin Inc., Shanghai, China). The solvents were dried before usage according to standard procedures [56]. Melting points (mp) were measured using a Büchi B-545 melting point apparatus (BÜCHI Labortechnik AG, Flawil, Switzerland). Microwave-assisted reactions were carried out in a Nova-2S microwave reactor (PreeKem Scientific Instruments Co.,Ltd., Shanghai, China) in sealed vessels at a constant temperature. Gradient column chromatography was performed using SepaBean™ machine T (Santai Science Inc., Montréal, QC, Canada).
1H, 13C{1H} and 19F NMR spectra were obtained with Bruker Avance-400 (Bruker Corporation, Karlsruhe, Germany). Chemical shifts for 1H NMR and 13C NMR spectroscopic data were referenced to the residual solvent resonance. Chemical shifts for 19F NMR spectroscopic data were referenced to PhCF3 (δ = − 63.72 ppm) added to analyzed samples as an internal standard. Spectroscopic data are presented in the following order: chemical shift, multiplicity, spin-spin coupling constant (Hz), and integrated intensity, where br = broad, s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, dd = doublet of doublets, ddd = doublet of doublet of doublets, dt = doublet of triplets, tt = triplet of triplets, ddt = doublet of doublet of triplets. The reactions were monitored by 19F NMR spectroscopy using a Magritek Spinsolve 60 MHz spectrometer (Magritek GmbH, Aachen, Germany).
Electronic absorption spectra were recorded on Agilent Cary 60 UV–vis (Agilent Technologies, Inc., Santa Clara, CA, USA) and JASCO V-770 UV-vis-NIR spectrophotometers (JASCO, Easton, MD, USA) in quartz cuvettes with an optical path length of 10 mm. Concentrations of the analyzed solutions were ~10−4 M. Emission spectra were recorded on a Hitachi F-2700 fluorescence spectrophotometer (Hitachi Ltd., Tokyo, Japan) with xenon lamp as excitation source in a 10 mm quartz cuvette. Concentrations of the analyzed solutions were ~10−6 M.

3.2. Fluorescence Quantum Yields

Fluorescence quantum yields (ΦF) were determined by the comparative method. The solution of Rhodamine 6G in EtOH (ΦF = 0.94) was used as a standard [57]. Both the samples and standard were excited at the same wavelength (490 nm). The absorbance of the solutions at the excitation wavelength is always below 0.1. Experiments were carried out at room temperature.
Equation (1) was employed for the calculations:
Φ F = Φ F   ( s t ) S · A s t · n 2 S s t · A · n s t 2  
where S and Sst are the areas under the fluorescence emission curves of the samples and the standard, respectively; A and Ast are the respective absorbances of the samples and standard at the excitation wavelengths, respectively; n and nst are refractive indexes of solvents in which the samples and standard are dissolved, respectively.

3.3. Singlet Oxygen Generation Measurements

Singlet oxygen generation measurements were performed using halogen-deuterium lamp (DH-2000, Ocean Optics, Inc., Orlando, FL, USA), monochromator MS 2004i (SOL Instruments, Minsk, Belarus), and fibre optics spectrophotometer AvaSpec-ULS2048CL-EVORS-UA (Avantes B.V., Apeldoorn, The Netherlands) and a thermostatically controlled cell holder CUV-UV/VIS-TCABS/FL (Ocean Optics, Inc., Orlando, FL, USA) with stirring. The light intensity was the same at all excitation wavelengths and was 2.43 × 1016 photon × s−1 × cm−2.
Singlet oxygen quantum yields (Φ∆) were determined in air in acetonitrile solutions using the relative method with Methylene Blue (in acetonitrile) as a reference. A singlet oxygen trap DPBF in acetonitrile was added to BODIPY solutions in acetonitrile (2.5 mL) in 10 mm quartz cuvettes equipped with caps, and its concentration did not exceed 2.5 × 10−5 M to prevent chain reactions [58]. The resulting solutions were irradiated at 555 nm and DPBF degradation at 410 nm was monitored. The constant temperature (25 °C) and continuous stirring (1200 rpm) were provided during the irradiation. Singlet oxygen quantum yields (ΦΔ) were calculated according to the following equation:
Φ Δ = Φ Δ ( s t ) × R R s t × 1 − 10 − A s t 1 − 10 − A  
where ΦΔ(st) is the quantum yields of singlet oxygen generation for the standard—Methylene blue (ΦΔ(st) = 0.52) [59]; R is rate of photobleaching of DPBF under irradiation; A is optical density of BODIPY at the irradiation wavelength.

3.4. Electrochemical Measurements

Electrochemical measurements were performed using an IPC_Pro M potentiostat (Volta, Saint Petersburg, Russia) in a three-electrode system. A glassy carbon and gold disks (d = 2 mm) were used as the working electrode. Ag/AgCl/KCl (aq., sat.) was used as a reference electrode. In turn, a platinum plate was used as an auxiliary electrode. A solution of Bu4NClO4 (0.1 M) in MeCN was used as the supporting electrolyte. The working electrode surface was polished by alumina powder with a particle size of less than 0.5 µm (Sigma-Aldrich, St. Louis, MO, USA). In the CV measurements, the potential sweep rate was 100 mV·s–1. In studies with the rotating disk electrode (RDE) method, the potential sweep rate is 20 mV·s–1. The potentials are presented with iR-compensation. The number of transferred electrons in redox processes was determined by comparing the peak current in the substrate and the current of single-electron oxidation of ferrocene taken in the same concentration. All measurements were carried out in a dry argon atmosphere. Samples were dissolved in a dry, pre-deaerated solvent at 22 °C. The concentration of solutions of BODIPYs 5 was ~10−3 M.

3.5. Synthesis and Characterization

General Procedure for the Barton−Zard Reaction of β-Fluoro-β-nitrostyrenes with 2-isocyanoacetamide.
A solution of a selected 2-isocyanoacetamide (5.6 mmol, 2 mol equiv) and DBU (0.837 mL, 5.6 mmol, 2 mol equiv) in DCM (28 mL) was prepared and loaded into a round-bottom flask equipped with a dropping funnel. Then, a solution of (Z)-(2-fluoro-2-nitrovinyl)benzene (0.468 g, 2.8 mmol, 1 mol equiv) in DCM (57 mL) was added dropwise to the vigorously stirred reaction mixture at room temperature over 2 h. After completion of the reaction (TLC monitoring), a 5% aqueous solution of HCl (100 mL) was added to the reaction mixture to hydrolyze the residual 2-isocyanoacetamide. The resulting mixture was vigorously stirred for 2 h. Next, the organic layer was separated and the water layer was extracted with DCM (2 × 50 mL). The combined organic phase was dried over anhydrous Na2SO4, filtered and concentrated under a vacuum. The residue was separated by column chromatography on silica gel using gradient elution to obtain the desired pyrrole 2 and pyrrole 3 as a side-product.
N-butyl-4-fluoro-3-phenyl-1H-pyrrole-2-carboxamide (2a). Eluent: Hex/EtOAc (9:1), Hex/EtOAc (6:1), Hex/EtOAc (3:1). Yield: 0.357 g (50%). Orange solid; mp 110–112 °C. 1H NMR (400 MHz, CDCl3): δ 10.62 (br s, 1H), 7.50–7.38 (m, 5H), 6.75 (t, J = 3.5 Hz, 1H), 5.70 (t, J = 4.9 Hz, 1H), 3.25 (q, J = 6.8 Hz, 2H), 1.31 (dt, J = 14.8, 7.0 Hz, 2H), 1.21–1.08 (m, 2H), 0.83 (t, J = 7.3 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 161.3 (d, 4JCF = 2.5 Hz), 149.6 (d, 1JCF = 242.9 Hz), 131.2 (d, 3JCF = 2.0 Hz), 130.5, 129.2, 128.3, 118.7 (d, 3JCF = 2.3 Hz), 113.0 (d, 2JCF = 12.9 Hz), 105.1 (d, 2JCF = 27.0 Hz), 39.0, 31.2, 19.9, 13.7. 19F NMR (376 MHz, CDCl3): δ −169.02 (s, 1F). HRMS (ESI) m/z: [M + H]+ calcd. for C15H18FN2O+ 261.1398; found 261.1400.
N-butyl-4-nitro-3-phenyl-1H-pyrrole-2-carboxamide (3a). Eluent: Hex/EtOAc (9:1), Hex/EtOAc (6:1), Hex/EtOAc (3:1). Yellow solid; mp 113–115 °C. Yield: 0.101 g (13%). 1H NMR (400 MHz, CDCl3): δ 11.28 (br s, 1H), 7.81 (s, 1H), 7.60–7.46 (m, 3H), 7.45–7.34 (m, 2H), 5.43 (br s, 1H), 3.17 (q, J = 6.2 Hz, 2H), 1.26–1.13 (m, 2H), 1.09–0.96 (m, 2H), 0.79 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 160.3, 135.9, 131.4, 130.1, 129.4, 129.2, 123.7, 122.0, 120.9, 39.2, 30.9, 19.8, 13.6. HRMS (ESI) m/z: [M + H]+ calcd. for C15H18N3O3+ 288.1343; found 288.1343.
N-cyclopropyl-4-fluoro-3-phenyl-1H-pyrrole-2-carboxamide (2b). Eluent: Hex/EtOAc (4:1). Yield: 0.170 g (25%). Sandy solid; mp 182–184 °C. 1H NMR (400 MHz, DMSO-d6): δ 11.42 (s, 1H), 7.43–7.36 (m, 4H), 7.35–7.27 (m, 1H), 7.16–7.05 (m, 1H), 6.90 (t, J = 3.4 Hz, 1H), 2.67 (dt, J = 10.4, 3.5 Hz, 1H), 0.65–0.56 (m, 2H), 0.37–0.30 (m, 2H). 13C{1H} NMR (100 MHz, DMSO-d6): δ 161.9, 148.8 (d, 1JCF = 239.7 Hz), 131.3 (d, 3JCF = 2.5 Hz), 129.7, 128.2, 127.0, 119.7 (d, 3JCF = 3.2 Hz), 112.5 (d, 2JCF = 11.7 Hz), 104.3 (d, 2JCF = 26.9 Hz), 22.4, 5.9. 19F NMR (376 MHz, DMSO-d6): δ −171.74 (s, 1F). HRMS (ESI) m/z: [M + H]+ calcd. for C14H14FN2O+ 245.1085; found 245.1086.
N-allyl-4-fluoro-3-phenyl-1H-pyrrole-2-carboxamide (2c). The pure product was isolated by column chromatography with gradient elution on silica gel using SepaBean™ machine T. Polarity of the elution system was gradually increased from Hex/EtOAc (9:1) to Hex/EtOAc (1:1). Yield: 0.260 g (37%). Dark yellow solid; mp 104–106 °C. 1H NMR (400 MHz, CDCl3): δ 10.96 (s, 1H), 7.54–7.36 (m, 5H), 6.79 (t, J = 3.6 Hz, 1H), 5.88 (t, J = 5.6 Hz, 1H), 5.73 (ddt, J = 22.4, 10.5, 5.3 Hz, 1H), 5.03 (dd, J = 10.4, 1.2 Hz, 1H), 4.96 (dd, J = 17.2, 1.3 Hz, 1H), 3.96–3.84 (m, 2H). 13C{1H} NMR (100 MHz, CDCl3): δ 161.3 (d, 4JCF = 2.4 Hz), 149.4 (d, 1JCF = 242.8 Hz), 133.5, 131.0 (d, 3JCF = 1.8 Hz), 130.3, 129.1, 128.2, 118.2 (d, 3JCF = 2.2 Hz), 115.8, 113.3 (d, 2JCF = 12.8 Hz), 105.6 (d, 2JCF = 26.9 Hz), 41.5. 19F NMR (376 MHz, CDCl3): δ −169.18 (s, 1F). HRMS (ESI) m/z: [M + H]+ calcd. for C14H14FN2O+ 245.1085; found 245.1086.
N-allyl-4-nitro-3-phenyl-1H-pyrrole-2-carboxamide (3c). The pure product was isolated by column chromatography with gradient elution on silica gel using SepaBean™ machine T. Polarity of the elution system was gradually increased from Hex/EtOAc (9:1) to Hex/EtOAc (1:1). Yield: 0.074 g (9%). Yellow solid; mp 158–160 °C. 1H NMR (400 MHz, CDCl3): δ 11.70 (br s, 1H), 7.83 (s, 1H), 7.58–7.46 (m, 3H), 7.45–7.36 (m, 2H) 5.71–5.49 (m, 2H), 5.00 (d, J = 10.2 Hz, 1H), 4.82 (d, J = 17.1 Hz, 1H), 3.81 (s, 2H). 13C{1H} NMR (100 MHz, CDCl3): δ 160.4, 135.8, 132.8, 131.2, 130.0, 129.4, 129.3, 123.4, 122.4, 121.3, 116.2, 41.7. HRMS (ESI) m/z: [M + H]+ calcd. for C14H14N3O3+ 272.1030; found 272.1030.
Procedure for the Scaled-Up Preparation of 2d.
A solution of N-benzyl-2-isocyanoacetamide (4.607 g, 26.4 mmol, 2 mol equiv) and DBU (3.955 mL, 26.4 mmol, 2 mol equiv) in DCM (134 mL) was prepared and loaded into a round-bottom flask equipped with a dropping funnel. Then, a solution of (Z)-(2-fluoro-2-nitrovinyl)benzene (2.210 g, 13.2 mmol, 1 mol equiv) in DCM (267 mL) was added dropwise to the vigorously stirred reaction mixture at room temperature over 6 h. After completion of the reaction (TLC monitoring), 5% aqueous solution of HCl (400 mL) was added to the reaction mixture to hydrolyze the residual N-benzyl-2-isocyanoacetamide. The resulting mixture was vigorously stirred for 2 h. Next, the organic layer was separated and the water layer was extracted with DCM (2 × 200 mL). The combined organic phase was dried over anhydrous Na2SO4, filtered and concentrated under a vacuum. The residue was separated by column chromatography on silica gel using SepaBean™ machine T to obtain the desired pyrrole 2d and pyrrole 3d as a side-product. The polarity of the elution system was gradually increased from Hex/EtOAc (9:1) to Hex/EtOAc (1:1), and then EtOAc was used.
N-benzyl-4-fluoro-3-phenyl-1H-pyrrole-2-carboxamide (2d). Yield: 0.658 g (17%). Viscous oil. 1H NMR (400 MHz, CDCl3): δ 10.10 (s, 1H), 7.46–7.22 (m, 8H), 7.10 (m, 2H), 6.71 (t, J = 3.4 Hz, 1H), 6.05 (t, J = 5.6 Hz, 1H), 4.45 (d, J = 5.8 Hz, 2H). 13C{1H} NMR (100 MHz, CDCl3): δ 161.1 (d, 4JCF = 2.6 Hz), 149.7 (d, 1JCF = 243.5 Hz), 137.8, 130.9 (d, 3JCF = 1.7 Hz), 130.4, 129.2, 128.7, 128.4, 127.5, 127.5, 118.5 (d, 3JCF = 2.1 Hz), 113.4 (d, 2JCF = 12.9 Hz), 105.3 (d, 2JCF = 27.1 Hz), 43.5. 19F NMR (376 MHz, CDCl3): δ −168.68 (pseudo-t, 3JHF = 4JHF = 3.0 Hz, 1F). HRMS (ESI) m/z: [M + H]+ calcd. for C18H16FN2O+ 295.1241; found 295.1243.
N-benzyl-4-nitro-3-phenyl-1H-pyrrole-2-carboxamide (3d). Yield: 0.448 g (11%). Orange viscous oil. 1H NMR (400 MHz, CDCl3) δ 11.72 (s, 1H), 7.69 (d, J = 3.8 Hz, 1H), 7.47–7.24 (m, 8H), 7.00–6.93 (m, 2H), 5.84 (t, J = 5.4 Hz, 1H), 4.34 (d, J = 5.6 Hz, 2H). 13C{1H} NMR (100 MHz, CDCl3) δ 160.0, 136.4, 135.3, 130.6, 129.5, 128.8, 128.7, 128.3, 127.3, 126.7, 122.8, 122.0, 120.9, 43.3. HRMS (ESI) m/z: [M + H]+ calcd. for C18H16N3O3+ 322.1186; found 322.1188.
Procedure for the Scaled-Up Preparation of 2e.
A solution of 2-isocyano-1-morpholinoethanone (5.486 g, 35.6 mmol, 2 mol equiv) and DBU (5.322 mL, 35.6 mmol, 2 mol equiv) in DCM (180 mL) was prepared and loaded into a round-bottom flask equipped with a dropping funnel. Then, a solution of (Z)-(2-fluoro-2-nitrovinyl)benzene (2.974 g, 17.8 mmol, 1 mol equiv) in DCM (359 mL) was added dropwise to the vigorously stirred reaction mixture at room temperature over 8 h. After completion of the reaction (TLC monitoring), 5% aqueous solution of HCl (500 mL) was added to the reaction mixture to hydrolyze the residual 2-isocyano-1-morpholinoethanone. The resulting mixture was vigorously stirred for 2 h. Next, the organic layer was separated and the water layer was extracted with DCM (2 × 250 mL). The combined organic phase was dried over anhydrous Na2SO4, filtered and concentrated under a vacuum. The residue was separated by column chromatography on silica gel using SepaBean™ machine T to obtain the desired pyrrole 2d and pyrrole 3d as a side-product. The polarity of the elution system was gradually increased from Hex/EtOAc (2:1) to Hex/EtOAc (1:4).
(4-Fluoro-3-phenyl-1H-pyrrol-2-yl)(morpholino)methanone (2e). Yield: 2.604 g (53%). Yellow solid; mp 209–211 °C. 1H NMR (400 MHz, CDCl3): δ 10.02 (s, 1H), 7.46–7.30 (m, 5H), 6.73 (t, J = 3.1 Hz, 1H), 3.33 (br s, 8H). 13C{1H} NMR (100 MHz, CDCl3): δ 164.0 (d, 4JCF = 2.0 Hz), 149.0 (d, 1JCF = 243.5 Hz), 131.7 (d, 3JCF = 2.4 Hz), 129.3, 129.0, 127.6, 118.0 (d, 3JCF = 2.9 Hz), 113.7 (d, 2JCF = 12.1 Hz), 105.0 (d, 2JCF = 27.5 Hz), 66.1, 66.1. 19F NMR (376 MHz, CDCl3): δ −170.39 (pseudo-t, 3JHF = 4JHF = 3.1 Hz, 1F). HRMS (ESI) m/z: [M + H]+ calcd. for C15H16FN2O2+ 275.1190; found 275.1190.
Morpholino(4-nitro-3-phenyl-1H-pyrrol-2-yl)methanone (3e). Yield: 0.980 g (18%). Dark yellow solid; mp 213–215 °C. 1H NMR (400 MHz, CDCl3): δ 11.61 (s, 1H), 7.84 (d, J = 3.6 Hz, 1H), 7.49–7.35 (m, 5H), 3.76–2.55 (m, 8H). 13C{1H} NMR (100 MHz, CDCl3): δ 162.9, 134.6, 131.1, 130.6, 128.8, 128.7, 123.2, 123.0, 121.3, 65.8, 65.7. HRMS (ESI) m/z: [M + H]+ calcd. for C15H16N3O4+ 302.1135; found 302.1136.
General Procedure for the Preparation of Dipyrromethanes 4.
In a typical experiment, a selected pyrrole 2 (0.4–1.4 mmol, 1 mol equiv) and a corresponding aldehyde (0.4–1.4 mmol, 1 mol equiv) were loaded into a suitable vial and dissolved in DCM (2–7 mL). In the case of obtaining dipyrromethane 4b, EtOAc was used instead of DCM. Then triflic acid (0.4–1.4 mmol, 1 mol equiv) was added to the reaction mixture and the resulting mixture was stirred for 24 h. Progress of the reaction was monitored by TLC or 19F NMR spectroscopy. After completion of the reaction, the reaction mixture was diluted with EtOAc (50–100 mL) and extracted with water (3 × (50–100) mL). Then, the organic layer was separated, dried over Na2SO4, filtered and concentrated under a vacuum. The pure product was isolated by column chromatography on silica gel using appropriate elution mixtures.
5,5′-((2,4,5-Trimethylphenyl)methylene)bis(N-butyl-4-fluoro-3-phenyl-1H-pyrrole-2-carboxamide) (4a). The pure product was isolated by column chromatography with gradient elution on silica gel using SepaBean™ machine T. Polarity of the elution system was gradually increased from DCM/EtOAc (99:1) to DCM/EtOAc (4:1). Yield: 0.135 g (83%). Orange solid; mp 208–210 °C. 1H NMR (400 MHz, CDCl3): δ 10.14 (br s, 2H), 7.46–7.33 (m, 10H), 7.14 (s, 1H), 6.94 (s, 1H), 5.87 (s, 1H), 5.64 (t, J = 5.4 Hz, 2H), 3.22–3.08 (m, 4H), 2.30 (s, 3H), 2.19 (s, 3H), 2.17 (s, 3H), 1.28–1.15 (m, 4H), 1.14–1.01 (m, 4H), 0.77 (t, J = 7.3 Hz, 6H). 13C{1H} NMR (100 MHz, CDCl3): δ 160.8 (d, 4JCF = 2.5 Hz), 146.3 (d, 1JCF = 244.4 Hz), 135.8, 134.7, 134.2, 133.1, 132.3, 131.2 (d, 3JCF = 1.9 Hz), 130.5, 129.5, 129.1, 128.2, 117.3 (d, 2JCF = 21.4 Hz), 117.1 (d, 3JCF = 2.2 Hz), 113.3 (d, 2JCF = 12.4 Hz), 39.0, 34.3, 31.1, 20.0, 19.7, 19.4, 19.0, 13.7. 19F NMR (376 MHz, CDCl3): δ −168.15 (s, 2F). HRMS (ESI) m/z: [M + H]+ calcd. for C40H45F2N4O2+ 651.3505; found 651.3505.
5,5′-((2,4,5-Trimethylphenyl)methylene)bis(N-cyclopropyl-4-fluoro-3-phenyl-1H-pyrrole-2-carboxamide) (4b). The pure product was isolated by column chromatography with gradient elution on silica gel using SepaBean™ machine T. Polarity of the elution system was gradually increased from DCM/EtOAc (98:2) to DCM/EtOAc (2.3:1). Yield: 0.087 g (78%). Orange solid; mp 160–162 °C. 1H NMR (400 MHz, CDCl3): δ 10.74 (br s, 2H), 7.36 (s, 10H), 7.25 (s, 1H), 6.94 (s, 1H), 5.94 (s, 1H), 5.73 (d, J = 3.3 Hz, 2H), 2.70 (dt, J = 10.6, 3.5 Hz, 2H), 2.32 (s, 3H), 2.18 (s, 3H), 2.14 (s, 3H), 0.57 (q, J = 6.2 Hz, 4H), 0.16 (q, J = 6.6 Hz, 4H). 13C{1H} NMR (100 MHz, CDCl3): δ 162.1, 146.2 (d, 1JCF = 244.2 Hz), 135.6, 134.5, 134.4, 133.2, 132.1, 131.1 (d, 3JCF = 1.5 Hz), 130.4, 129.8, 128.9, 128.2, 118.0 (d, 2JCF = 20.8 Hz), 116.9 (d, 3JCF = 2.4 Hz), 113.5 (d, 2JCF = 12.0 Hz), 34.3, 22.4, 19.6, 19.4, 19.1, 6.5, 6.5. 19F NMR (376 MHz, CDCl3): δ −167.94 (s, 2F). HRMS (ESI) m/z: [M + H]+ calcd. for C38H37F2N4O2+ 619.2879; found 619.2881.
5,5′-((2,4,5-Trimethylphenyl)methylene)bis(N-allyl-4-fluoro-3-phenyl-1H-pyrrole-2-carboxamide) (4c). The pure product was isolated by column chromatography with gradient elution on silica gel using SepaBean™ machine T. Polarity of the elution system was gradually increased from DCM/EtOAc (98:2) to DCM/EtOAc (3:1). Yield: 0.103 g (68%). Sandy solid; mp 237–239 °C. 1H NMR (400 MHz, CDCl3): δ 11.07 (br s, 2H), 7.43–7.30 (m, 11H), 6.95 (s, 1H), 5.94 (s, 1H), 5.78 (t, J = 5.3 Hz, 2H), 5.61 (ddt, J = 22.6, 10.7, 5.5 Hz, 2H), 4.96 (d, J = 10.3 Hz, 2H), 4.85 (d, J = 17.2 Hz, 2H), 3.86–3.69 (m, 4H), 2.37 (s, 3H), 2.20 (s, 3H), 2.18 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 160.7 (d, 4JCF = 2.6 Hz), 146.4 (d, 1JCF = 244.0 Hz), 135.5, 134.6, 134.5, 133.5, 133.0, 132.0, 131.2 (d, 3JCF = 1.8 Hz), 130.4, 129.9, 129.1, 128.1, 118.3 (d, 2JCF = 20.2 Hz), 116.5 (d, 3JCF = 2.5 Hz), 116.2, 113.5 (d, 2JCF = 12.0 Hz), 41.8, 34.4, 19.6, 19.4, 19.1. 19F NMR (376 MHz, CDCl3): δ −168.08 (s, 2F). HRMS (ESI) m/z: [M + H]+ calcd. for C38H37F2N4O2+ 619.2879; found 619.2879.
5,5′-((2,4,5-Trimethylphenyl)methylene)bis(N-benzyl-4-fluoro-3-phenyl-1H-pyrrole-2-carboxamide) (4d). The pure product was isolated by column chromatography with gradient elution on silica gel using SepaBean™ machine T. Polarity of the elution system was gradually increased from DCM/EtOAc (99:1) to DCM/EtOAc (9:1). Yield: 0.179 g (56%). Sandy solid; mp 126–128 °C. 1H NMR (400 MHz, CDCl3): δ 11.46 (br s, 2H), 7.56 (s, 1H), 7.33–7.23 (m, 12H), 7.19 (t, J = 7.4 Hz, 4H), 7.02 (s, 1H), 7.02–6.96 (m, 4H), 6.10 (s, 1H), 6.06 (t, J = 5.2 Hz, 2H), 4.48–4.31 (m, 4H), 2.47 (s, 3H), 2.24 (s, 3H), 2.22 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 160.8 (d, 4JCF = 2.4 Hz), 146.4 (d, 1JCF = 244.3 Hz), 137.2, 135.4, 134.8, 134.4, 133.1, 131.9, 130.9 (d, 3JCF = 1.9 Hz), 130.3, 130.1, 128.9, 128.6, 127.9, 127.7, 127.4, 118.6 (d, 2JCF = 20.2 Hz), 116.5 (d, 3JCF = 2.6 Hz), 113.6 (d, 2JCF = 12.0 Hz), 43.7, 34.4, 19.5, 19.4, 19.2. 19F NMR (376 MHz, CDCl3): δ −167.90 (s, 2F). HRMS (ESI) m/z: [M + H]+ calcd. for C46H41F2N4O2+ 719.3192; found 719.3192.
(5,5′-((2,4,5-Trimethylphenyl)methylene)bis(4-fluoro-3-phenyl-1H-pyrrole-5,2-diyl))bis(morpholinomethanone) (4e). Eluent: Hex/EtOAc (1:1), EtOAc. Yield: 0.261 g (84%). Orange solid; mp 180–182 °C. 1H NMR (400 MHz, CDCl3): δ 9.40 (br s, 2H), 7.42–7.27 (m, 10H), 7.05 (s, 1H), 6.95 (s, 1H), 5.89 (s, 1H), 3.21 (br s, 16H), 2.29 (s, 3H), 2.18 (s, 3H), 2.14 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 163.6, 145.5 (d, 1JCF = 244.0 Hz), 136.0, 134.8, 134.0, 133.2, 132.5, 131.5, 129.3, 129.1, 128.9, 127.7, 117.0 (d, 2JCF = 21.6 Hz), 116.5 (d, 3JCF = 3.6 Hz), 114.3 (d, 2JCF = 10.3 Hz), 65.9, 65.9, 34.1, 19.6, 19.4, 19.0. 19F NMR (376 MHz, CDCl3): δ −169.47 (s, 2F). HRMS (ESI) m/z: [M + H]+ calcd. for C40H41F2N4O4+ 679.3090; found 679.3090.
(5,5′-(Phenylmethylene)bis(4-fluoro-3-phenyl-1H-pyrrole-5,2-diyl))bis(morpholinomethanone) (4f). Eluent: Hex/EtOAc (1:1), EtOAc. Yield: 0.125 g (97%). Colourless solid; mp 194–196 °C. 1H NMR (400 MHz, CDCl3): δ 10.77 (s, 2H), 7.41–7.28 (m, 10H), 7.13 (d, J = 7.2 Hz, 2H), 7.10–7.00 (m, 3H), 5.90 (s, 1H), 3.22 (br s, 16H). 13C{1H} NMR (100 MHz, CDCl3): δ 163.9 (d, 4JCF = 2.1 Hz), 145.9 (d, 1JCF = 243.9 Hz), 139.5, 131.6 (d, 3JCF = 2.5 Hz), 129.4, 128.9, 128.6, 127.7, 127.6, 127.2, 117.4 (d, 2JCF = 22.4 Hz), 117.0 (d, 3JCF = 3.6 Hz), 113.7 (d, 2JCF = 11.7 Hz), 65.9, 65.9, 36.1. 19F NMR (376 MHz, CDCl3): δ −171.02 (s, 2F). HRMS (ESI) m/z: [M + H]+ calcd. for C37H35F2N4O4+ 637.2621; found 637.2621.
(5,5′-(O-tolylmethylene)bis(4-fluoro-3-phenyl-1H-pyrrole-5,2-diyl))bis(morpholinomethanone) (4g). Eluent: Hex/EtOAc (1:1), EtOAc. Yield: 0.130 g (quant.). Pale pink solid; mp 184–186 °C. 1H NMR (400 MHz, CDCl3): δ 10.47 (s, 2H), 7.42–7.25 (m, 11H), 7.10 (d, J = 7.1 Hz, 1H), 7.04 (t, J = 7.2 Hz, 1H), 6.91 (t, J = 7.3 Hz, 1H), 5.97 (s, 1H), 3.22 (br s, 16H), 2.33 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 163.8 (d, 4JCF = 2.1 Hz), 145.4 (d, 1JCF = 244.0 Hz), 137.4, 136.1, 131.6 (d, 3JCF = 2.2 Hz), 130.9, 129.3, 128.8, 127.9, 127.5, 127.4, 126.4, 117.0 (d, 2JCF = 21.3 Hz), 116.8 (d, 3JCF = 3.1 Hz), 113.7 (d, 2JCF = 11.7 Hz), 65.9, 65.9, 34.0, 19.6. 19F NMR (376 MHz, CDCl3): δ −170.16 (s, 2F). HRMS (ESI) m/z: [M + H]+ calcd. for C38H37F2N4O4+ 651.2777; found 651.2777.
(5,5′-((2,4-Dichlorophenyl)methylene)bis(4-fluoro-3-phenyl-1H-pyrrole-5,2-diyl))bis(morpholinomethanone) (4h). Eluent: Hex/EtOAc (1:1), EtOAc. Yield: 0.141 g (quant.). Powdery solid; mp 195–197 °C. 1H NMR (400 MHz, CDCl3): δ 10.87 (s, 2H), 7.42–7.25 (m, 12H), 6.93 (dd, J = 8.4, 2.0 Hz, 1H), 6.19 (s, 1H), 3.22 (br s, 16H). 13C{1H} NMR (100 MHz, CDCl3): δ 163.7 (d, 4JCF = 2.0 Hz), 145.7 (d, 1JCF = 245.0 Hz), 135.7, 134.3, 133.6, 131.4 (d, 3JCF = 2.3 Hz), 130.7, 129.6, 129.0, 128.9, 127.6, 127.3, 117.1 (d, 3JCF = 3.7 Hz), 115.6 (d, 2JCF = 21.4 Hz), 113.5 (d, 2JCF = 11.6 Hz), 65.8, 65.8, 34.4. 19F NMR (376 MHz, CDCl3): δ −169.19 (s, 2F). HRMS (ESI) m/z: [M + H]+ calcd. for C37H33Cl2F2N4O4+ 705.1841; found 705.1841.
(5,5′-((2,5-Dimethoxyphenyl)methylene)bis(4-fluoro-3-phenyl-1H-pyrrole-5,2-diyl))bis(morpholinomethanone) (4i). Eluent: Hex/EtOAc (1:1), EtOAc. Yield: 0.138 g (quant.). Sandy solid; mp 212–214 °C. 1H NMR (400 MHz, CDCl3): δ 10.38 (s, 2H), 7.39–7.23 (m, 10H), 6.87 (d, J = 2.9 Hz, 1H), 6.83 (d, J = 8.9 Hz, 1H), 6.71 (dd, J = 8.9, 3.0 Hz, 1H), 6.04 (s, 1H), 3.77 (s, 3H), 3.61 (s, 3H), 3.19 (br s, 16H). 13C{1H} NMR (100 MHz, CDCl3): δ 163.7 (d, 4JCF = 2.0 Hz), 153.6, 151.1, 145.2 (d, 1JCF = 244.0 Hz), 131.7 (d, 3JCF = 2.2 Hz), 129.3, 129.2, 128.7, 127.3, 116.7 (d, 2JCF = 22.1 Hz), 116.5, 116.5 (d, 3JCF = 3.9 Hz), 113.6 (d, 2JCF = 11.7 Hz), 112.4, 111.7, 65.9, 65.9, 56.6, 55.5, 32.1. 19F NMR (376 MHz, CDCl3): δ −170.19 (s, 2F). HRMS (ESI) m/z: [M + H]+ calcd. for C39H39F2N4O6+ 697.2832; found 697.2832.
(5,5′-((2,4,5-Trimethoxyphenyl)methylene)bis(4-fluoro-3-phenyl-1H-pyrrole-5,2-diyl))bis(morpholinomethanone) (4j). Eluent: Hex/EtOAc (1:1), EtOAc, EtOAc/EtOH (98:2). Yield: 0.140 g (96%). Pale orange solid; mp 192–194 °C. 1H and 19F NMR spectra of the sample are complex due to the presence of two sets of signals corresponding to two stable rotamers in a ratio of 75:25. In 1H spectra some similar signals overlap. 1H NMR (400 MHz, CDCl3): δ 11.27 (br s, 1H), 10.04 (br s, 1H), 7.43–7.20 (m, 10H), 7.05 (s, 1H), 6.60 (s, 1H), 5.95 (s, 1H), 3.88 (s, 3H), 3.86 (s, 3H), 3.78 (s, 3H), 3.20 (br s, 16H). 13C{1H} NMR (100 MHz, CDCl3): δ 163.8 (d, 4JCF = 1.0 Hz), 151.1, 149.3, 145.3 (d, 1JCF = 243.8 Hz), 143.5, 131.7 (d, 3JCF = 2.5 Hz), 128.9, 128.8, 128.6, 127.4, 127.3, 119.4, 117.1 (d, 2JCF = 21.4 Hz), 116.3 (d, 3JCF = 3.6 Hz), 114.1, 113.2 (d, 2JCF = 11.5 Hz), 66.0, 65.8, 57.3, 56.6, 56.2. 19F NMR (376 MHz, CDCl3): major rotamer δ −170.4 (s, 1F); minor rotamer δ -171.9 (s, 1F). HRMS (ESI) m/z: [M + H]+ calcd. for C40H41F2N4O7+ 727.2938; found 727.2938.
General Procedure for the Preparation of BODIPYs 5.
In a typical experiment, a selected dipyrromethane 4 (0.15 mmol, 1 mol equiv) and DDQ (0.102 g, 0.45 mmol, 3 mol equiv) were loaded into a screw cap vial (30 mL) for the microwave reactor Nova-2S (PreeKem) and dissolved in MeCN (7.5 mL). The reaction mixture was heated under microwave irradiation at 60 °C for 15 min with stirring. After completion of the oxidation step (monitoring by TLC or 19F NMR spectroscopy), the reaction mixture was cooled to room temperature. Then, triethylamine (0.209 mL, 1.5 mmol, 10 mol equiv) was added and the resulting mixture was stirred for 3 min. Next, BF3⋅Et2O (0.278 mL, 2.25 mmol, 15 mol equiv) was added to the reaction mixture. The vial with the resulting mixture was purged with argon and then heated under microwave irradiation at 60 °C for 40 min with stirring. After completion of the reaction (monitoring by TLC or 19F NMR spectroscopy), the reaction mixture was diluted with EtOAc (100 mL) and extracted with water (5 × 100 mL). Then, the organic layer was separated, dried over Na2SO4, filtered and concentrated under a vacuum. The pure product was isolated by column chromatography on silica gel using appropriate eluents.
3,7-Bis(butylcarbamoyl)-1,5,5,9-tetrafluoro-2,8-diphenyl-10-(2,4,5-trimethylphenyl)-5H-dipyrrolo[1,2-c:2′,1′-f][1,3,2]diazaborinin-4-ium-5-uide (5a). The pure product was isolated by column chromatography with gradient elution on silica gel using SepaBean™ machine T (Santai Science Inc., Montréal, QC, Canada). Polarity of the elution system was gradually increased from DCM/EtOAc (98:2) to DCM/EtOAc (96:4). Yield: 0.031 g (27%). Red solid; mp 219–221 °C. 1H NMR (400 MHz, CDCl3): δ 7.46–7.40 (m, 4H), 7.38–7.27 (m, 6H), 7.09 (s, 1H), 7.02 (s, 1H), 6.64 (br s, 2H), 3.45 (q, J = 6.8 Hz, 4H), 2.29 (s, 3H), 2.25 (s, 6H), 1.60 (dt, J = 15.0, 7.5 Hz, 4H), 1.44–1.33 (m, 4H), 0.94 (t, J = 7.4 Hz, 6H). 13C NMR (100MHz, CDCl3): δ 160.6, 159.4 (d, 1JCF = 287.5 Hz), 147.5, 146.7, 139.0, 134.4, 132.6, 131.8, 128.8, 128.6, 128.6, 128.4, 128.0 (d, 3JCF = 1.8 Hz), 127.3, 121.0 (d, 2JCF = 11.2 Hz), 118.3 (d, 2JCF = 7.4 Hz), 40.1, 31.2, 20.2, 19.8, 19.4, 19.2, 13.8. 19F NMR (376 MHz, CDCl3): δ −132.19 (s, 2F), −136.36–−136.81 (m, 2F). HRMS (ESI) m/z: [M + H]+ calcd. for C40H42BF4N4O2+ 697.3331; found 697.3331.
3,7-Bis(cyclopropylcarbamoyl)-1,5,5,9-tetrafluoro-2,8-diphenyl-10-(2,4,5-trimethylphenyl)-5H-dipyrrolo[1,2-c:2′,1′-f][1,3,2]diazaborinin-4-ium-5-uide (5b). The pure product was isolated by column chromatography with gradient elution on silica gel using SepaBean™ machine T (Santai Science Inc., Montréal, QC, Canada). Polarity of the elution system was gradually increased from DCM/EtOAc (98:2) to DCM/EtOAc (96:4). Yield: 0.028 g (30%). Red solid; mp 195–197 °C. 1H NMR (400 MHz, CDCl3): δ 7.46–7.40 (m, 4H), 7.40–7.28 (m, 6H), 7.09 (s, 1H), 6.99 (s, 1H), 6.70 (s, 1H), 6.69 (s, 1H), 2.89 (dt, J = 10.5, 3.5 Hz, 2H), 2.29 (s, 3H), 2.24 (s, 3H), 2.23 (s, 3H), 0.91–0.85 (m, 4H), 0.75–0.68 (m, 4H). 13C{1H} NMR (100 MHz, CDCl3): δ 162.0, 159.4 (d, 1JCF = 282.3 Hz), 147.2, 146.9, 139.1, 134.4, 132.5, 131.9, 128.8, 128.7, 128.6, 128.5, 127.9 (d, 3JCF = 2.0 Hz), 127.2, 121.0 (d, 2JCF = 12.7 Hz), 118.4 (d, 2JCF = 8.8 Hz), 23.1, 19.8, 19.3, 19.1, 6.8. 19F NMR (376 MHz, CDCl3): δ −131.80 (s, 2F), −135.74–−136.17 (m, 2F). HRMS (ESI) m/z: [M + Na]+ calcd. for C38H33BF4N4NaO2+ 687.2525; found 687.2525.
3,7-Bis(allylcarbamoyl)-1,5,5,9-tetrafluoro-2,8-diphenyl-10-(2,4,5-trimethylphenyl)-5H-dipyrrolo[1,2-c:2′,1′-f][1,3,2]diazaborinin-4-ium-5-uide (5c). The pure product was isolated by column chromatography with gradient elution on silica gel using SepaBean™ machine T (Santai Science Inc., Montréal, QC, Canada). Polarity of the elution system was gradually increased from DCM/EtOAc (98:2) to DCM/EtOAc (96:4). Yield: 0.018 g (20%). Red solid; mp 253–255 °C (with decomp.). 1H NMR (400 MHz, CDCl3): δ 7.43 (d, J = 6.9 Hz, 4H), 7.39–7.28 (m, 6H), 7.10 (s, 1H), 7.03 (s, 1H), 6.73 (br s, 2H), 5.90 (ddt, J = 22.6, 10.8, 5.7 Hz, 2H), 5.28 (dd, J = 17.2, 1.0 Hz, 2H), 5.18 (dd, J = 10.3, 0.9 Hz, 2H), 4.09 (t, J = 5.7 Hz, 4H), 2.30 (s, 3H), 2.26 (s, 6H). 13C{1H} NMR (100 MHz, CDCl3): δ 160.5, 159.5 (d, 1JCF = 285.0 Hz), 147.1, 147.0, 139.1, 134.4, 133.1, 132.6, 131.9, 128.8, 128.7, 128.6, 128.5, 127.9 (d, 3JCF = 1.5 Hz), 127.3, 121.1 (d, 2JCF = 13.5 Hz), 118.55 (d, 2JCF = 9.7 Hz), 117.4, 42.7, 19.9, 19.4, 19.2. 19F NMR (376 MHz, CDCl3): δ −131.91 (s, 2F), −135.64–−136.76 (m, 2F). HRMS (ESI) m/z: [M + H]+ calcd. for C38H34BF4N4O2+ 665.2705; found 665.2706.
3,7-Bis(benzylcarbamoyl)-1,5,5,9-tetrafluoro-2,8-diphenyl-10-(2,4,5-trimethylphenyl)-5H-dipyrrolo[1,2-c:2′,1′-f][1,3,2]diazaborinin-4-ium-5-uide (5d). The pure product was isolated by column chromatography with gradient elution on silica gel using SepaBean™ machine T (Santai Science Inc., Montréal, QC, Canada). Polarity of the elution system was gradually increased from DCM/EtOAc (99:1) to DCM/EtOAc (17:1). Yield: 0.016 g (51%), 0.045 g (46%). Red solid; mp 223–225 °C. 1H NMR (400 MHz, CDCl3): δ 7.41–7.27 (m, 20H), 7.09 (s, 1H), 7.01 (s, 1H), 6.88 (br s, 2H), 4.64 (d, J = 5.7 Hz, 4H), 2.29 (s, 3H), 2.25 (s, 3H), 2.24 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 160.7, 159.3 (d, 1JCF = 286.7 Hz), 147.1 (d, 3JCF = 1.9 Hz), 147.0, 139.1, 137.1, 134.4, 132.6, 131.8, 128.8, 128.7, 128.6, 128.4, 128.2, 128.0 (d, 3JCF = 3.8 Hz), 127.8, 127.8, 127.2, 121.1 (d, 2JCF = 11.8 Hz), 118.4 (d, 2JCF = 9.4 Hz), 44.3, 19.8, 19.3, 19.1.19F NMR (376 MHz, CDCl3): δ −131.99 (s, 2F), −136.55–−137.14 (m, 2F). HRMS (ESI) m/z: [M + H]+ calcd. for C46H38BF4N4O2+ 765.3018; found 765.3020.
1,5,5,9-Tetrafluoro-3,7-di(morpholine-4-carbonyl)-2,8-diphenyl-10-(2,4,5-trimethylphenyl)-5H-dipyrrolo[1,2-c:2′,1’-f][1,3,2]diazaborinin-4-ium-5-uide (5e). The pure product was isolated by column chromatography with gradient elution on silica gel using SepaBean™ machine T (Santai Science Inc., Montréal, QC, Canada). Polarity of the elution system was gradually increased from DCM/EtOAc (98:2) to DCM/EtOAc (3:1). Yield: 0.098 g (90%). Red solid; mp 298–300 °C. The NMR spectra of the sample are complex due to the presence of two sets of signals corresponding to two stable rotamers in ratio 1:1, where many similar signals overlap. 1H NMR (400 MHz, CDCl3): δ 7.43 (d, J = 7.4 Hz, 4H), 7.41–7.29 (m, 6H), 7.10 (s, 1H), 7.02 (s, 1H), 3.92–3.26 (m, 12H), 3.04–2.91 (m, 2H), 2.85–2.67 (m, 2H), 2.29 (s, 3H), 2.27 (s, 3H), 2.24 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 160.8, 160.7, 158.8 (d, 1JCF = 285.7 Hz), 158.4 (d, 1JCF = 284.8 Hz), 147.1, 146.7, 146.1, 139.2, 134.3, 132.9, 131.9, 129.2, 129.0, 128.7, 127.9, 127.7 (d, 3JCF = 2.5 Hz), 127.1, 121.4 (d, 2JCF = 12.3 Hz), 116.2 (d, 2JCF = 9.2 Hz), 66.1, 66.0, 47.0, 42.2, 42.2, 19.8, 19.3, 19.2. 19F NMR (376 MHz, CDCl3): δ −131.57 (s, 1F), −133.29 (s, 1F), −142.27–−143.52 (m, 2F). HRMS (ESI) m/z: [M + H]+ calcd. for C40H38BF4N4O4+ 725.2917; found 725.2917.
1,5,5,9-Tetrafluoro-3,7-di(morpholine-4-carbonyl)-2,8,10-triphenyl-5H-dipyrrolo[1,2-c:2′,1′-f][1,3,2]diazaborinin-4-ium-5-uide (5f). The pure product was isolated by column chromatography with gradient elution on silica gel using SepaBean™ machine T (Santai Science Inc., Montréal, QC, Canada). Polarity of the elution system was gradually increased from DCM/EtOAc (98:2) to DCM/EtOAc (2:1). Yield: 0.083 g (82%). Red solid; mp 316–318 °C. 1H NMR (400 MHz, CDCl3): δ 7.63–7.47 (m, 5H), 7.46–7.29 (m, 10H), 3.89–3.79 (m, 2H), 3.78–3.47 (m, 6H), 3.43–3.26 (m, 4H), 3.03–2.91 (m, 2H), 2.73 (t, J = 8.4 Hz, 2H). 13C NMR (100 MHz, CDCl3): δ 160.6, 158.6 (d, 1JCF = 286.6 Hz), 147.3, 145.9, 131.1, 129.8, 129.0, 128.8, 128.6, 128.5, 127.9, 127.6, 121.0 (d, 2JCF = 11.9 Hz), 116.4 (d, 2JCF = 9.5 Hz), 66.1, 66.0, 47.0, 42.2. 19F NMR (376 MHz, CDCl3): δ −130.54 (s, 2F), −142.77 (dd, J = 58.8, 28.7 Hz, 2F). HRMS (ESI) m/z: [M + H]+ calcd. for C37H32BF4N4O4+ 683.2447; found 683.2448.
1,5,5,9-Tetrafluoro-3,7-di(morpholine-4-carbonyl)-2,8-diphenyl-10-(o-tolyl)-5H-dipyrrolo[1,2-c:2′,1′-f][1,3,2]diazaborinin-4-ium-5-uide (5g). The pure product was isolated by column chromatography with gradient elution on silica gel using SepaBean™ machine T (Santai Science Inc., Montréal, QC, Canada). Polarity of the elution system was gradually increased from DCM/EtOAc (98:2) to DCM/EtOAc (2:1). Yield: 0.081g (77%). Red solid; mp 324–326 °C (with decomp.). The NMR spectra of the sample are complex due to the presence of two sets of signals corresponding to two stable rotamers in ratio 1:1, where many similar signals overlap. 1H NMR (400 MHz, CDCl3): δ 7.46–7.26 (m, 14H), 3.88–3.78 (m, 2H), 3.78–3.60 (m, 4H), 3.59–3.48 (m, 2H), 3.46–3.26 (m, 4H), 3.04–2.91 (m, 2H), 2.85–2.70 (m, 2H), 2.35 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 160.6, 160.6, 158.9 (d, 1JCF = 280.5 Hz), 158.8 (d, 1JCF = 289.3 Hz), 147.5, 147.2, 145.3, 135.6, 130.5, 130.4, 129.7, 129.0, 128.8, 128.1, 127.8, 127.6, 126.0, 121.3 (d, 2JCF = 12.3 Hz), 121.2 (d, 2JCF = 13.5 Hz), 116.3 (d, J = 8.6 Hz), 66.1, 66.0, 47.0, 42.2, 42.2, 19.8. 19F NMR (376 MHz, CDCl3): δ −131.79 (s, 1F), −133.28 (s, 1F), −142.92 (ddd, J = 39.5, 28.5, 10.0 Hz, 2F). HRMS (ESI) m/z: [M + H]+ calcd. for C38H34BF4N4O4+ 697.2604; found 697.2604.
10-(2,4-Dichlorophenyl)-1,5,5,9-tetrafluoro-3,7-di(morpholine-4-carbonyl)-2,8-diphenyl-5H-dipyrrolo[1,2-c:2′,1′-f][1,3,2]diazaborinin-4-ium-5-uide (5h). The pure product was isolated by column chromatography with gradient elution on silica gel using SepaBean™ machine T (Santai Science Inc., Montréal, QC, Canada). Polarity of the elution system was gradually increased from DCM/EtOAc (98:2) to DCM/EtOAc (3:1). The NMR spectra of the sample are complex due to the presence of two sets of signals corresponding to two stable rotamers in ratio 53:47, where many similar signals overlap. Yield: 0.098 g (88%). Violet solid; mp 186–188 °C. 1H NMR (400 MHz, CDCl3): δ 7.57 (d, J = 1.9 Hz, 1H), 7.46–7.31 (m, 12H), 3.88–3.60 (m, 6H), 3.60–3.48 (m, 2H), 3.45–3.26 (m, 4H), 3.06–2.91 (m, 2H), 2.86–2.71 (m, 2H). 13C{1H} NMR (100 MHz, CDCl3): δ 160.4, 158.6 (d, 1JCF = 283.8 Hz), 158.5 (d, 1JCF = 285.6 Hz), 148.3, 139.7, 137.3, 133.6, 130.7, 130.1, 129.1, 128.9, 127.9, 127.7, 127.6, 127.4 (d, 3JCF = 3.4 Hz), 127.3 (d, 3JCF = 3.9 Hz), 121.2 (d, 2JCF = 9.4 Hz), 121.1 (d, 2JCF = 13.1 Hz), 116.6 (d, 2JCF = 10.2 Hz), 116.5 (d, 2JCF = 9.4 Hz), 66.1, 66.0, 47.0, 42.0, 42.2. 19F NMR (376 MHz, CDCl3): −132.40 (s, 1F), −132.84 (s, 1F), −141.90–−142.60 (m, 1F), −143.21–−143.90 (m, 1F). HRMS (ESI) m/z: [M + H]+ calcd. for C37H30BCl2F4N4O4+ 751.1668; found 751.1669.
10-(2,4-Dimethoxyphenyl)-1,5,5,9-tetrafluoro-3,7-di(morpholine-4-carbonyl)-2,8-diphenyl-5H-dipyrrolo[1,2-c:2′,1′-f][1,3,2]diazaborinin-4-ium-5-uide (5i). The pure product was isolated by column chromatography with gradient elution on silica gel using SepaBean™ machine T (Santai Science Inc., Montréal, QC, Canada). Polarity of the elution system was gradually increased from DCM/EtOAc (98:2) to DCM/EtOAc (3:1). Yield: 0.086 g (76%). Violet solid; mp 325–327 °C (with decomp.). The NMR spectra of the sample are complex due to the presence of two sets of signals corresponding to two stable rotamers in ratio 1:1, where many similar signals overlap. 1H NMR (400 MHz, CDCl3): δ 7.47–7.29 (m, 10H), 7.04 (dd, J = 9.0, 3.0 Hz, 1H), 6.94 (d, J = 9.1 Hz, 1H), 6.86 (d, J = 2.1 Hz, 1H), 3.87–3.79 (m, 2H), 3.76 (s, 3H), 3.74 (s, 3H), 3.77–3.58 (m, 4H), 3.57–3.46 (m, 2H), 3.43–3.25 (m, 4H), 3.03–2.89 (m, 2H), 2.80–2.67 (m, 2H). 13C{1H} NMR (100 MHz, CDCl3): δ 160.8, 160.7, 158.6 (d, 1JCF = 285.8 Hz), 153.4, 151.1, 146.8, 146.6, 142.4, 129.0, 128.7, 127.9, 127.8 (d, 3JCF = 3.2 Hz), 121.8 (d, 2JCF = 13.3 Hz), 121.3 (d, 2JCF = 13.3 Hz), 119.4, 117.4, 116.1 (d, 2JCF = 7.2 Hz), 116.0 (d, 2JCF = 8.7 Hz), 115.6, 112.0 (s), 66.1, 66.0, 56.1, 55.9, 47.0, 42.2, 42.1. 19F NMR (376 MHz, CDCl3): δ −131.24 (s, 1F), −133.17 (s, 1F), −141.53–−142.36 (m, 1F), −143.23–−143.96 (m, 1F). HRMS (ESI) m/z: [M + Na]+ calcd. for C39H35BF4N4NaO6+ 765.2478; found 765.2479.
1,5,5,9-Tetrafluoro-3,7-di(morpholine-4-carbonyl)-2,8-diphenyl-10-(2,4,5-trimethoxyphenyl)-5H-dipyrrolo[1,2-c:2′,1′-f][1,3,2]diazaborinin-4-ium-5-uide (5j). The pure product was isolated by column chromatography with gradient elution on silica gel using SepaBean™ machine T (Santai Science Inc., Montréal, QC, Canada). Polarity of the elution system was gradually increased from DCM/EtOAc (6:1) to DCM/EtOAc (3:1). Yield: 0.064 g (56%). Violet solid; mp 195–197 °C. The NMR spectra of the sample are complex due to the presence of two sets of signals corresponding to two stable rotamers in ratio 1:1, where many similar signals overlap. 1H NMR (400 MHz, CDCl3): δ 7.47–7.30 (m, 10H), 6.82 (d, J = 2.3 Hz, 1H), 6.59 (s, 1H), 3.97 (s, 3H), 3.79 (s, 3H), 3.88–3.68 (m, 4H), 3.77 (s, 3H), 3.67–3.56 (m, 2H), 3.55–3.44 (m, 2H), 3.41–3.23 (m, 4H), 3.00–2.87 (m, 2H), 2.74–2.62 (m, 2H). 13C{1H} (100 MHz, CDCl3): δ 160.9, 160.8, 158.3 (d, 1JCF = 283.2 Hz), 158.1 (d, 1JCF = 285.5 Hz), 152.8, 152.6, 146.1, 145.8, 143.1, 142.8, 129.0, 128.6 (d, 3JCF = 3.5 Hz), 128.0 (d, 3JCF = 2.9 Hz), 128.0, 127.9, 127.8, 122.0 (d, 2JCF = 12.4 Hz), 121.1 (d, 2JCF = 11.8 Hz), 116.0 (d, 2JCF = 9.6 Hz), 115.9 (d, 2JCF = 7.9 Hz), 113.9 (d, J = 3.6 Hz), 109.7, 96.4, 66.1, 66.0, 66.0, 56.6, 56.2, 56.2, 47.0, 42.2, 42.1. 19F NMR (376 MHz, CDCl3): δ −131.45 (s, 1F), −133.70 (s, 1F), −141.55–−142.33 (m, 1F), −143.09–−143.77 (m, 1F). HRMS (ESI) m/z: [M + Na]+ calcd. for C40H37BF4N4NaO7+ 795.2584; found 795.2585.
Procedure for the Preparation of BODIPYs 5k.
Diethyl 5,5′-((2,4,5-trimethylphenyl)methylene)bis(4-fluoro-3-phenyl-1H-pyrrole-2-carboxylate) (0.090 g, 0.15 mmol, 1 mol equiv) and DDQ (0.102 g, 0.45 mmol, 3 mol equiv) were loaded into a screw cap vial (30 mL) for the microwave reactor Nova-2S (PreeKem) and dissolved in MeCN (7.5 mL). The reaction mixture was heated under microwave irradiation at 80 °C for 2 h with stirring. After completion of the oxidation step (TLC monitoring), the reaction mixture was cooled to room temperature. Then, triethylamine (0.209 mL, 1.5 mmol, 10 mol equiv) was added and the resulting mixture was stirred for 3 min. Next, BF3⋅Et2O (0.278 mL, 2.25 mmol, 15 mol equiv) was added to the reaction mixture. The vial with the resulting mixture was purged with argon and then heated under microwave irradiation at 80 °C for 2 h with stirring.
After completion of the reaction (TLC monitoring), the reaction mixture was diluted with EtOAc (100 mL) and extracted with water (5 × 100 mL). Then, the organic layer was separated, dried over Na2SO4, filtered and concentrated under a vacuum. The pure product was isolated by column chromatography with gradient elution on silica gel using SepaBean™ machine T (Santai Science Inc., Montréal, QC, Canada). Polarity of the elution system was gradually increased from Hex to Hex/EtOAc (1:1).
3,7-Bis(ethoxycarbonyl)-1,5,5,9-tetrafluoro-2,8-diphenyl-10-(2,4,5-trimethylphenyl)-5H-dipyrrolo[1,2-c:2′,1′-f][1,3,2]diazaborinin-4-ium-5-uide (5k). Yield: 0.055 g (57%). Red solid; mp 210–212 °C. 1H NMR (400 MHz, CDCl3): δ 7.42–7.27 (m, 10H), 7.10 (s, 1H), 7.04 (s, 1H), 4.41 (q, J = 7.1 Hz, 4H), 2.29 (s, 3H), 2.27 (s, 3H), 2.26 (s, 3H), 1.30 (t, J = 7.1 Hz, 6H). 13C{1H} NMR (100 MHz, CDCl3): δ 161.2, 159.3 (d, 1JCF = 285.5 Hz), 148.1, 144.2, 139.2, 134.3, 132.7, 131.9, 128.8, 128.6, 128.6, 128.5, 128.0 (d, 3JCF = 1.4 Hz), 127.3, 121.90 (d, 2JCF = 10.5 Hz), 118.3 (d, 2JCF = 10.2 Hz), 62.9, 19.8, 19.3, 19.1, 13.8. 19F NMR (376 MHz, CDCl3): δ −131.29 (s, 2F), −141.20–−141.92 (m, 1F), −142.12–−142.82 (m, 1F). HRMS (ESI) m/z: [M + Na]+ calcd. for C36H31BF4N2NaO4+ 665.2205; found 665.2207.

4. Conclusions

In summary, the efficient synthetic route to novel 1,7-difluoro-BODIPY-3,5-diamides 5 based on sequential transformation on β-fluoro-β-nitrostyrene 1 was developed. This modular approach allowed the introduction of fluorine atoms strictly into the 1,7-positions of the BODIPY core. A new family of BODIPYs 5 with various amide groups at the 3,5-positions and aryl substituents at the 8-position was prepared in up to 90% yield.
The photophysical properties of the obtained BODIPYs 5 were investigated. The solvatofluorochromic effect was observed upon transition from polar solvents to nonpolar ones. The largest bathochromic (18 nm) and bathofloral shifts (13 nm) for BODIPY 5a were observed in toluene compared to methanol. In addition, it was found that less polar solvents are more favourable for fluorescent properties. The largest value of ΦF for 5a was achieved in THF (0.16), while the lowest value was observed in methanol (0.04). The obtained dyes showed the absorption maxima in the range of 531–545 nm, the emission maxima in the range of 577–597 nm, ΦF in up to 0.17 and ΦΔ in up to 0.16 in THF solutions.
The photophysical and electrochemical properties of 1,7-difluoro-BODIPY-3,5-diamides were compared with their analogues to study the substituent effect at the 3,5-positions. It was found that the amide groups provide much higher ΦF (0.16) compared to ethoxycarbonyl ones (0.03), but significantly lower ΦF compared to methyl ones (0.60). On the other hand, both amide and ester and methyl derivatives showed moderate photosensitizing properties in MeCN (ΦΔ = 0.15–0.22). All compared dyes demonstrated similar electrochemical properties: reduction occurs in two one-electron stages, the first of which is reversible, oxidation is more than one-electron and irreversible. Both the reduction and oxidation potentials increase with a rise of the electron-withdrawing ability of 3,5-substituents from −1.32 to −0.82 V and from 0.95 to 1.29 V, respectively. In turn, DFT studies revealed the influence of 3,5-substituents on the electronic structures of these molecules.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/ijms26104484/s1.

Author Contributions

Conceptualization, A.S.A. and V.G.N.; methodology, V.E.S., E.A.S.; formal analysis, A.S.A., A.A.M., V.E.S. and E.A.S.; investigation, V.E.S. and S.R.M.; data curation, S.R.M. and V.E.S.; writing—original draft preparation, A.S.A. and V.E.S.; writing—review and editing, V.G.N. and Y.G.G.; visualization, A.A.M., E.A.S., V.E.S. and S.R.M.; supervision, A.S.A., V.G.N. and Y.G.G.; project administration, A.S.A. and V.G.N., funding acquisition, V.G.N. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by the Russian Science Foundation, grant number 23-73-00014.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Data are contained within the article and Supplementary Materials.

Acknowledgments

This work was supported in part by M.V. Lomonosov Moscow State University Program of Development. Preliminary NMR spectra were recorded using a Magritek Spinsolve 60 MHz spectrometer (Istina MGU ID 545023931). We appreciate V.A. Chertkov for providing the Gaussian 16 program.

Conflicts of Interest

The authors declare no conflicts of interest.

References

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Ijms 26 04484 g001
Figure 1. Families of core-fluorinated BODIPYs synthesized starting from β-fluoro-β-nitrostyrenes.
Figure 1. Families of core-fluorinated BODIPYs synthesized starting from β-fluoro-β-nitrostyrenes.
Ijms 26 04484 g001
Ijms 26 04484 sch001
Scheme 1. Barton-Zard reaction of β-fluoro-β-nitrostyrenes 1 with 2-isocyanoacetamides.
Scheme 1. Barton-Zard reaction of β-fluoro-β-nitrostyrenes 1 with 2-isocyanoacetamides.
Ijms 26 04484 sch001
Ijms 26 04484 sch002
Scheme 2. Preparation of BODIPYs 4 with different amido-groups.
Scheme 2. Preparation of BODIPYs 4 with different amido-groups.
Ijms 26 04484 sch002
Ijms 26 04484 sch003
Scheme 3. Preparation of BODIPYs 4 with different meso-aryl groups.
Scheme 3. Preparation of BODIPYs 4 with different meso-aryl groups.
Ijms 26 04484 sch003
Ijms 26 04484 g002
Figure 2. UV–vis absorption and emission spectra of solution of BODIPY 5e in THF.
Figure 2. UV–vis absorption and emission spectra of solution of BODIPY 5e in THF.
Ijms 26 04484 g002
Ijms 26 04484 g003
Figure 3. Cyclic voltammograms of BODIPYs 5a–5k at 100 mVs−1 in 0.1 M of Bu4NClO4 in CH3CN using GC as a stationary electrode. Peaks of the first redox processes: 5a—blue; 5e—green; 5l—black; 5k—red.
Figure 3. Cyclic voltammograms of BODIPYs 5a–5k at 100 mVs−1 in 0.1 M of Bu4NClO4 in CH3CN using GC as a stationary electrode. Peaks of the first redox processes: 5a—blue; 5e—green; 5l—black; 5k—red.
Ijms 26 04484 g003
Ijms 26 04484 g004
Figure 4. The optimized geometry of the ground electronic state of compounds, the frontier orbitals localization and EPMs of 5e, 5k and 5l.
Figure 4. The optimized geometry of the ground electronic state of compounds, the frontier orbitals localization and EPMs of 5e, 5k and 5l.
Ijms 26 04484 g004
Ijms 26 04484 g005
Figure 5. Frontier orbitals calculated for optimized geometry of selected BODIPYs.
Figure 5. Frontier orbitals calculated for optimized geometry of selected BODIPYs.
Ijms 26 04484 g005
Table 1. Photophysical properties of BODIPY 5a in different solvents.
Table 1. Photophysical properties of BODIPY 5a in different solvents.
EntrySolventDielectric Constantλabs (max),
nm		λem (max),
nm		Stokes
Shift, nm		ΦF 1
1Toluene2.4538584460.14
2Chloroform4.8534583490.12
3THF7.5533577440.16
4Acetone21.0527575480.09
5Methanol32.6520571510.04
6Acetonitrile36.6525 2575500.05
7DMSO47.0531581500.07
1 related to Rhodamin 6G in EtOH; 2 ε = 41,706 M−1·cm−1.
Table 2. Photophysical properties of BODIPYs 5a–5j.
Table 2. Photophysical properties of BODIPYs 5a–5j.
EntryCodeMeso-ArylAmido Group λabs
(max), nm 1		λem
(max), nm 1		Stokes
Shift, nm		ΦF 1,2ΦΔ 3
15a2,4,5-(Me)3C6H2Ijms 26 04484 i001533577440.160.10
25bIjms 26 04484 i002535577420.090.12
35cIjms 26 04484 i003531577460.140.16
45dIjms 26 04484 i004533577440.170.12
55eIjms 26 04484 i005531577460.120.15
65fC6H5Ijms 26 04484 i006533584510.01<0.05
75g2-MeC6H4533582490.160.10
85h2,4-(Cl)2C6H3545597520.030.09
95i2,5-(MeO)2C6H3535- 4---
105j2,4,5-(MeO)3C6H2533----
1 measured in THF; 2 related to Rhodamin 6G in EtOH; 3 measured in MeCN related to methylene blue; 4 not detected.
Table 3. Photophysical properties of 3,5-disubstituted core-fluorinated BODIPYs.
Table 3. Photophysical properties of 3,5-disubstituted core-fluorinated BODIPYs.
Ijms 26 04484 i007Ijms 26 04484 i008Ijms 26 04484 i009Ijms 26 04484 i010Ijms 26 04484 i011
BODIPY5a5e5k5l
λabs (max), nm 1533531525517
λem (max), nm 1577577581552
Stokes shift, nm44465635
ΦF 1,20.160.120.030.60
ΦΔ 30.100.150.180.22
1 measured in THF; 2 related to Rhodamin 6G in EtOH; 3 measured in MeCN related to methylene blue.
Table 4. Electrochemical potentials of 3,5-disubstituted core-fluorinated BODIPYs *.
Table 4. Electrochemical potentials of 3,5-disubstituted core-fluorinated BODIPYs *.
BODIPYXERed, VEOx, V
E1/2, V
I		Epc/2, V
II		Epa/2, V
I
5kIjms 26 04484 i012–0.82–1.751.29
5aIjms 26 04484 i013–0.93–1.841.18
5eIjms 26 04484 i014–1.07–2.131.16
5lIjms 26 04484 i015–1.32–2.300.95
* Measured in MeCN with 0.1 M Bu4NClO4 as supporting electrolyte; potentials were measured relative to Ag|AgCl|KCl aq. sat. reference electrode; the potentials of half-waves are shown for reversible redox processes; the potentials of half-peaks are shown for irreversible redox processes. Potential values are given regarding the potential of the redox process Fc/Fc+.
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Shambalova, V.E.; Mikheeva, S.R.; Aldoshin, A.S.; Moiseeva, A.A.; Safonova, E.A.; Gorbunova, Y.G.; Nenajdenko, V.G. Efficient Synthesis of Core-Fluorinated BODIPY-3,5-Diamides. Int. J. Mol. Sci. 2025, 26, 4484. https://doi.org/10.3390/ijms26104484

AMA Style

Shambalova VE, Mikheeva SR, Aldoshin AS, Moiseeva AA, Safonova EA, Gorbunova YG, Nenajdenko VG. Efficient Synthesis of Core-Fluorinated BODIPY-3,5-Diamides. International Journal of Molecular Sciences. 2025; 26(10):4484. https://doi.org/10.3390/ijms26104484

Chicago/Turabian Style

Shambalova, Victoria E., Sofiya R. Mikheeva, Alexander S. Aldoshin, Anna A. Moiseeva, Evgeniya A. Safonova, Yulia G. Gorbunova, and Valentine G. Nenajdenko. 2025. "Efficient Synthesis of Core-Fluorinated BODIPY-3,5-Diamides" International Journal of Molecular Sciences 26, no. 10: 4484. https://doi.org/10.3390/ijms26104484

APA Style

Shambalova, V. E., Mikheeva, S. R., Aldoshin, A. S., Moiseeva, A. A., Safonova, E. A., Gorbunova, Y. G., & Nenajdenko, V. G. (2025). Efficient Synthesis of Core-Fluorinated BODIPY-3,5-Diamides. International Journal of Molecular Sciences, 26(10), 4484. https://doi.org/10.3390/ijms26104484

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