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Pd-Catalyzed Direct C-H Functionalization/Annulation of BODIPYs with Alkynes to Access Unsymmetrical Benzo[b]-Fused BODIPYs: Discovery of Lysosome-Targeted Turn-On Fluorescent Probes Xiuguang Yang, Linfeng Jiang, Mufan Yang, Huaxing Zhang, Jingbo Lan, Fulin Zhou, Xingyu Chen, Di Wu, and Jingsong You J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01239 • Publication Date (Web): 06 Jul 2018 Downloaded from http://pubs.acs.org on July 6, 2018

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The Journal of Organic Chemistry

Pd-Catalyzed Direct C−H Functionalization/Annulation of BODIPYs

with

Alkynes

to

Access

Unsymmetrical

Benzo[b]-Fused BODIPYs: Discovery of Lysosome-Targeted Turn-On Fluorescent Probes Xiuguang Yang, Linfeng Jiang, Mufan Yang, Huaxing Zhang, Jingbo Lan,* Fulin Zhou, Xingyu Chen, Di Wu,* and Jingsong You Key Laboratory of Green Chemistry and Technology of Ministry of Education, College of Chemistry, Sichuan University, 29 Wangjiang Road, Chengdu 610064, PR China. E-mail: [email protected]; [email protected].

ABSTRACT: A highly

efficient palladium-catalyzed direct C−H functionalization/annulation

of BODIPYs with alkynes has been developed for the first time to construct a series of unsymmetrical benzo[b]-fused BODIPYs from readily available starting materials. These unsymmetrical benzo[b]-fused BODIPYs exhibit remarkably red-shifted emissions and larger Stokes shifts than classical BODIPY dyes. Cell imaging experiments and cytotoxicity assays demonstrate that BODIPYs 4c and 4d have specific lysosome-labeling capacities, turn-on fluorescence emissions in cell, and low cytotoxicity. Boron-dipyrromethene (BODIPY) is an important and versatile class of fluorophores with a wide range of applications, such as fluorescent probes,1 photodynamic therapy,2 laser dyes,3 and organic photovoltaic materials.4 BODIPY-based dyes have many excellent features,

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including high molar absorption coefficients and fluorescence quantum yields, narrow emission bandwidths, excitation wavelengths located in the visible light region, resistance towards self-aggregation, good solubility, chemical and photochemical stability, and thus have gained evergrowing attention.1,2,4,5 However, the emission wavelength of classical BODIPY dyes lies in the green light region.6 Moreover, BODIPY dyes typically have rather small Stokes shifts, which may lead to serious self-quenching and fluorescence detection errors due to backscattering effects from the excitation source.7 BODIPY derivatives are rarely applied as electroluminescence materials due to the weak solid fluorescence perhaps induced by the self-quenching.8 The common strategy for addressing these issues is the extension of the π-conjugation by the introduction of (hetro)aryl group and the fusion of aromatic ring to the BODIPY core, as well as the electronic desymmetrization by the construction of unsymmetrically substituted D-A type BODIPYs.5,9 Fusions at α- and β-positions of BODIPYs to construct aromatic ring fused BODIPY scaffolds have proven to be very effective methods in altering the electronic spectroscopies (Scheme 1).10 Scheme 1. Selected Examples of BODIPY Derivatives

In recent years, numerous of b bond-fused BODIPY dyes have been prepared starting from fused pyrroles or through the postmodification/annulation of the BODIPY core (Scheme 2).10c,11 However, both kinds of pathways usually involve multistep reactions, inaccessible synthetic precursors or unavoidable prefunctionalization. From the viewpoint of

efficiency

and

step

economy,

the

transition

metal-catalyzed

direct

C−H

functionalization/annulation of BODIPYs is doubtless a more ideal strategy to access benzo[b]-fused

BODIPYs.

Recently,

the

transition

metal-catalyzed

direct

C−H

functionalization of BODIPYs has made much progress,12 which may serve as guidance


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cues for the direct C−H functionalization/annulation of BODIPYs with alkynes. In addition, the direct C−H functionalization/annulation of arenes with alkynes has also been developed to accomplish various benzannulations.13 However, the direct C−H activation of BODIPY and the subsequent addition/annulation with two alkyne molecules to construct benzo[b]-fused BODIPY scaffolds remains an unresolved issue so far. Herein, we report the first example of palladium-catalyzed C−H functionalization/annulation of BODIPYs with alkynes to access a series of aryl or carboxylic ester-substituted unsymmetrical benzo[b]-fused BODIPYs for screening potential lysosome-targeted reagents (Scheme 2). Scheme 2. Synthesis of b Bond-Fused BODIPYs

Palladium-catalyzed C−H activation has emerged as a powerful strategy to accomplish various direct C−H functionalization reactions.14 Pd(OAc)2 and Ag2CO3 are the most frequently used catalyst and oxidant in such reactions.12f,15 Therefore, an initial investigation into the C−H functionalization/annulation of BODIPY (1a) with 1,2-diphenylethyne (2a) was conducted using the Pd(OAc)2/Ag2CO3 catalyst system. Delightedly, the annulation product (3a) fused at α- and β-positions of the BODIPY core was obtained in 35% yield by using benzoic acid as an additive and 1,3,5-trimethylbenzene as solvent at 120 °C for 12 h under an N2 atmosphere (Table 1, entry 1). The structure of 3a was confirmed by nuclear magnetic resonance (NMR) spectroscopy, high resolution mass spectrometry (HRMS), and



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single-crystal X-ray diffraction analysis (Scheme 3). After screening other palladium catalysts, Pd(PhCN)2Cl2 was found to have the same catalytic activity with Pd(OAc)2 (Table 1, entry 6). Moreover, in the absence of the additive, 3a could be obtained in 52% yield with silver 2,2-dimethylpropanoate (AgOPiv) as an oxidant (Table 1, entry 12). Next, the screening of other solvents, reaction temperature and reaction time was carried out, and the best result was obtained in 1,2-dichloroethane (DCE) at 120 °C for 12 h with Pd(PhCN)2Cl2 as a catalyst and AgOPiv as an oxidant under an N2 atmosphere, affording the desired product (3a) in 80% yield (Table 1, entry 13). Table

1.

Optimization

of

Pd-Catalyzed

Direct

C−H

Functionalization/Annulation

8-(p-Tolyl)-BODIPY with 1,2-Diphenylethynea

Temp.

Yieldb

(ºC)

(%)

mesitylene

120

35

PhCOOH

mesitylene

120

22

Ag2CO3

PhCOOH

mesitylene

120

N.D.

Pd2(dba)3

Ag2CO3

PhCOOH

mesitylene

120

trace

5

Pd(PPh3)2Cl2

Ag2CO3

PhCOOH

mesitylene

120

trace

6

Pd(PhCN)2Cl2

Ag2CO3

PhCOOH

mesitylene

120

35

7

Pd(PhCN)2Cl2

Ag2O

PhCOOH

mesitylene

120

trace

8

Pd(PhCN)2Cl2

AgOAc

PhCOOH

mesitylene

120

trace

9

Pd(PhCN)2Cl2

AgOPiv

PhCOOH

mesitylene

120

40

10

Pd(PhCN)2Cl2

AgOPiv

PivOH

mesitylene

120

32

11

Pd(PhCN)2Cl2

AgOPiv

CsOPiv

mesitylene

120

33

12

Pd(PhCN)2Cl2

AgOPiv

/

mesitylene

120

52

13

Pd(PhCN)2Cl2

AgOPiv

/

DCE

120

80

14

Pd(PhCN)2Cl2

AgOPiv

/

DMF

120

N.D.

15

Pd(PhCN)2Cl2

AgOPiv

/

toluene

120

52.

Entry

Pd source

Oxidant

Additive

Solvent

1

Pd(OAc)2

Ag2CO3

PhCOOH

2

PdCl2

Ag2CO3

3

Pd(TFA)2

4


of

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a

16

Pd(PhCN)2Cl2

AgOPiv

/

dioxane

120

57

17

Pd(PhCN)2Cl2

AgOPiv

/

DCE

140

63

18

Pd(PhCN)2Cl2

AgOPiv

/

DCE

100

50

19

Pd(PhCN)2Cl2

AgOPiv

/

DCE

120

80

20

Pd(PhCN)2Cl2

AgOPiv

/

DCE

120

50

Reaction conditions: 8-(p-Tolyl)-BODIPY (1a, 0.1 mmol), 1,2-diphenylethyne (2a, 3.0 equiv), [Pd] (10.0

mol%), oxidant (4.0 equiv), additive (0.5 equiv) and solvent (1.0 mL) at 120 ºC for 12 h under N2 atmosphere. b

Isolated yields. c 24 h. d 8 h. mesitylene = 1,3,5-trimethylbenzene, PivOH = 2,2-dimethylpropanoic acid, DCE

= 1,2-dichloroethane, DMF = N,N-dimethylformamide. N.D. = no detection. Scheme 3. Scope of Alkynes

Reaction conditions: 1a (0.1 mmol), 2 (0.3 mmol, 3.0 equiv), Pd(PhCN)2Cl2 (0.01 mmol, 10.0 mol%), silver 2,2-dimethylpropanoate (AgOPiv, 0.4 mmol, 4.0 equiv) and 1,2-dichloroethane (DCE, 1.0 mL) at 120 °C for



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12 h under an N2 atmosphere. Isolated yields.

Under the optimal conditions, the scope of alkyne substrates was examined. As summarized in Scheme 3, a range of diphenylethyne (2) with various functional groups such as methyl, methoxy, fluoro, chloro, bromo, and carboxylic ester group, smoothly underwent the direct C−H functionalization/annulation with BODIPY (1a), delivering the corresponding benzannulation products in moderate to good yields (Scheme 3, 3b−3i). In particular, this C−H functionalization/annulation reaction could tolerate reactive chloride and bromide, affording the desired products in synthetically useful yields (Scheme 3, 3g and 3h),

which

might

provide

opportunities

for

further

synthetic

transformations.

1,2-Di(naphthalen-2-yl)ethyne (2j) could also react with 1a to give 3j in 53% yield. Gratifyingly, dimethyl but-2-ynedioate (2k) could enable the desired reaction, affording 3k in 57% yields. Scheme 4. Scope of BODIPYs R

R

Pd(PhCN)2Cl2 (10 mol%) AgOPiv (4.0 equiv) N

B

N

Ph

Ph

+

DCE, 120 °C, 12 h

Ph N

F F

F F 2a

1

4

Ph B

N

Ph 4a 81%

N

B

N

N

Ph

F F

Ph 4b 82%

Ph

Ph

Ph

Ph

Ph

F F

Ph Ph

OC12H25

OMe

N

N

B

N

B

F F

Ph

Ph

Ph Ph

4c 52%

N

Ph N

B

N

F F

Ph

Ph

Ph

B

N

F F

Ph

Ph

Ph

Ph

4d 63% F3C

N

N

B

N

F F

Ph

Ph

4e 76%

4f 57%

CN

NO2

Ph Ph

CF3

Ph N

B

N

F F

Ph

4g 80%

Ph Ph

Ph N

B

N

F F

Ph

4h 76%

Ph

Ph N

B

N

F F

Ph

Ph

Ph Ph

4i 42%

Reaction conditions: 1 (0.1 mmol), 2a (0.3 mmol, 3.0 equiv), Pd(PhCN)2Cl2 (0.01 mmol, 10.0 mol%), silver


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2,2-dimethylpropanoate (AgOPiv, 0.4 mmol, 4.0 equiv) and 1,2-dichloroethane (DCE, 1.0 mL) at 120 °C for 12 h under an N2 atmosphere. Isolated yields.

Subsequently, the scope with respect to BODIPY derivatives was investigated (Scheme 4). BODIPYs with an electron-donating 4-methoxy, 4-dodecyloxy, 4-dimethylamino, 4-tert-butyl,

2,4,6-trimethyl

group

as

well

as

an

electron-withdrawing

3,5-bis(trifluoromethyl), 4-cyano and 4-nitro group on the meso-phenyl substituent underwent the direct C−H functionalization/annulation with 1,2-diphenylethyne (2a), giving the corresponding products in moderate to good yields (Scheme 4, 4b−4i). Especially, the nitro group, which could not be tolerated in many C−H activations, was compatible under this catalytic condition, delivering 4i in an acceptable yield. Scheme 5. Plausible Mechanism for Pd-Catalyzed Direct C−H Functionalization/Annulation of BODIPYs with Alkynes

On the basis of the reactivity pattern of various BODIPY substrates as well as previous reports,12,16 a plausible mechanism is shown in Scheme 5. Initially, the regioselective direct electrophilic palladation at the 2-position of BODIPY 1a forms BODIPY-2-ylpalladium species IM1. The 2 (or 6)-position of BODIPY is more electron-rich and thus is more



Page 8 of 28

susceptible to electrophilic attack12f. Next, the alkyne 2a inserts into the Pd-C bond of IM1 to produce a vinylpalladium species IM2. Subsequently, another molecular 2a inserts into the Pd-C bond of IM2 to afford the butadienylpalladium intermediate IM3, which undergoes an intramolecular electrophilic palladation at the 3-position of BODIPY to generate the intermediate IM4. Finally, the reductive elimination of IM4 releases the benzo[b]-fused BODIPY 3a and Pd(0) species. The Pd(0) species is eventually reoxidized by AgOPiv to generate Pd(Ⅱ) and accomplish the catalytic cycle. Table 2. Photophysical Properties of 1a, 3e, 3k, 4d and 4g Stokes Shift

Dyes

λabs (nm)a

λem (nm)b

(Фf)c

1a

499

520

0.01

809

3e

529

662

< 0.01

3798

3k

590

614

0.24

663

4d

518

622

< 0.01

3228

4g

543

638

< 0.01

2742

a

Absorption maximum in CH2Cl2 at 1 × 10–5 mol/L.

b

c

Absolute quantum yield determined in CH2Cl2 at 1 × 10–5 mol/L.

(cm-1)

Emission maximum in CH2Cl2 at 1 × 10–5 mol/L.

With a library of benzo[b]-fused BODIPYs in hand, their photophysical properties were investigated. Among these benzo[b]-fused BODIPYs, multiply ester-substituted derivative 3k shows high fluorescence quantum yield, up to 24% in dichloromethane solution (Table 2); while multiply aryl-substituted derivatives exhibit very low fluorescence quantum yields. Moreover, the fluorescence emissions of most of the multiply aryl-substituted benzo[b]-fused BODIPYs are so weak that their emission bands cannot be accurately detected. The emission wavelengths of benzo[b]-fused BODIPYs 3e, 4d and 4g can be detected, which exhibit remarkably red-shifted emission bands compared with 1a in solution (Table 2). By contrast with 1a, BODIPYs 3e, 4d and 4g exhibit larger Stokes shifts, perhaps due to the electronic desymmetrization. Next, the investigation of the live cell imaging experiments of benzo[b]-fused BODIPYs


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3k, 4c and 4d was conducted using human hepatoma HepG2 cells using fluorescence and laser scanning confocal microscopy. It was observed that incubation of 4c and 4d in HepG2 cell resulted in rapid uptake of 4c and 4d and localization in the lysosome, verified by co-localization studies with LysoTracker® Deep Red and LysoTracker® Green DND-26, respectively (Figure 1). The corresponding Pearson's correlation coefficient for 4c and 4d were 0.96 and 0.88, and the Mander's overlap coefficients were 0.93 and 0.89, respectively, indicating the selective labeling of the lysosome in HepG2 cells. Although 3k also success fully penetrated the cell membranes and labeled HepG2 cells with bright red luminescence, it did not exhibit the specificity of cell organelle-localization.

Figure 1. Fluorescent images of HepG2 cells: (A) Stained with 4c (λex = 543 nm, λem = 550-600 nm); (B) Stained with LysoTracker® Deep Red (λex = 633 nm, λem = 650-750 nm); (C) Merged image of A and B; (E) Stained with 4d (λex = 488 nm, λem = 600-700 nm); (F) Stained with LysoTracker® Green DND-26 (λex = 488 nm, λem = 500-550 nm); (G) Merged image of E and F; (D) and (H) Fluorescence intensity profiles of regions of interest across HepG2 cells for 4c and 4d, respectively.

Given that the emission of 4c is very weak in solution, but it exhibits bright fluorescent image in live cells (Figure 1A), and thus we hypothesized that the increasing intracellular viscosity or the chang of pH values (pH 4.5−5.5 in lysosomes)17 might result in a turn-on fluorescence emission of 4c. Therefore, the fluorescence intensities of 4c and 4d in methanol/glycerol mixtures with different ratios were measured,18 and the pH-dependencies of the fluorescence intensities of 4c and 4d were also investigated. It was observed that the pKa values of 4c and 4d are 3.9 and 3.7, respectively, and their fluorescence intensities are



not significantly changed in pH 4.5−5.5 (Figure S3). However, the fluorescence intensities of both compounds increase apparently in methanol/glycerol mixtures with the increasing ratio of glycerol to methanol (Figure S2), indicating the turn-on emission with increasing solvent viscosity. The cytotoxicity of BODIPYs 4c and 4d were assessed by cell viability assay. As shown in Fig. S5, 4c and 4d did not exhibit distinct toxicity to cultured HepG2 cells in the concentration range of 0.625 to 10 μM, indicating the potential practicability in the live cell imaging. CONCLUSION In summary, we have developed a highly efficient palladium-catalyzed direct C−H functionalization/annulation of BODIPYs with alkynes to construct a series of aryl or carboxylic ester-substituted unsymmetrical benzo[b]-fused BODIPY scaffolds. This protocol is compatible with chloro, bromo, carboxylic ester and nitro group, which provides opportunities for further synthetic transformations. Cell imaging experiments and cytotoxicity assays demonstrate that benzo[b]-fused BODIPYs 4c and 4d have specific lysosome-labeling capacities, turn-on fluorescence emissions in cell, and low cytotoxicity, which would be potential lysosome-targeted reagents. EXPERIMENTAL SECTION General Information. NMR spectra were obtained on an Agilent 400-MR DD2 spectrometer. The 1H NMR (400 MHz) chemical shifts were measured relative to CDCl3 or DMSO-d6 as the internal reference (CDCl3: δ = 7.26 ppm; DMSO-d6: δ = 2.50 ppm). The 13

C NMR (100 MHz) chemical shifts were given using CDCl3 or DMSO-d6 as the internal

standard (CDCl3: δ = 77.16 ppm; DMSO-d6: δ = 39.52 ppm). High resolution mass spectra (HRMS) were obtained with a Shimadzu LCMS-IT-TOF (ESI). X-Ray single-crystal diffraction data were collected on an Agilent Technologies Gemini single crystal


Page 10 of 28

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diffractometer. Melting points were determined with XRC-1 and are uncorrected. Absorption spectra were obtained on a HITACHI U-2910 spectrometer. Fluorescence spectra and absolute quantum yields were collected on a Horiba Jobin Yvon-Edison Fluoromax-4 fluorescence spectrometer with a calibrated integrating sphere system. To reduce the fluctuation in the excitation intensity, the lamp was kept on for 1 h prior to the experiment. The confocal living cell imaging was performed on a Zeiss LSM 780 confocal fluorescent microscope. Unless otherwise noted, all reagents were obtained from commercial suppliers and used without

further

purification.

(8-(p-tolyl)-BODIPY)19a

8-(p-Tolyl)-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene

(1a),

8-phenyl-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene

(8-phenyl-BODIPY)19a

(1b),

8-(p-methoxyphenyl)-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (8-(p-methoxyphenyl)-BODIPY)19b

(1c),

8-(p-dodecyloxy-phenyl)-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (8-(p-dodecyloxy-phenyl)-BODIPY)18

(1d),

8-(p-dimethylaminophenyl)-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (8-(p-dimethylaminophenyl)-BODIPY)19a

(1e),

8-(p-tert-butylphenyl)-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (8-(p-tert-butylphenyl)-BODIPY)19a 8-mesityl-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene

(1f), (8-mesityl-BODIPY)17c

(1g),

8-(3,5-bis(trifluoromethyl)phenyl)-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (8-(3,5-bis(trifluoromethyl)phenyl)-BODIPY)19d

(1h),

8-(p-cyano-phenyl)-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (8-(p-cyano-phenyl)-BODIPY)19e

(1i),

8-(4-nitrophenyl)-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (8-(4-nitrophenyl)-BODIPY)19c (1j), and most of the alkyne substrates20 were prepared according to the literature.



General Procedure for the Direct C–H Functionalization/Annulation of BODIPYs with Alkynes. A dried Schlenk tube with a magnetic stir bar was charged with BODIPY (1, 0.1 mmol), alkyne (2, 0.30 mmol, 3.0 equiv), Pd(PhCN)2Cl2 (10.0 mol%) and AgOPiv (4.0 equiv). The system was evacuated thrice and back filled with N2. Next, the solvent DCE (1.0 mL) was added via a syringe and the rubber septum was replaced with a polytetrafluoroethylene stopper under N2. Then the reaction mixture was stirred at the 120 °C for 12 h in an oil bath. After the reaction mixture was cooled to ambient temperature, the solvent was removed under reduced pressure. The residue was dissolved in 10 mL of CH2Cl2, filtered through a celite pad, and then washed with 20-30 mL of CH2Cl2. The combined filtrates were concentrated and purified via column chromatography on silica gel (100-200 mesh) to provide the desired products. meso-(p-Tolyl)-tetraphenylbenzo[b]-fused BODIPY (3a). Purification via column chromatography on silica gel (petroleum ether/ethyl acetate/dichloromethane = 12/1/1, v/v/v) afforded the product 3a (50.9 mg) in 80% yield as a black purple solid with a greenish metallic lustre. M.p.: > 250 °C. 1H NMR (400 MHz, CDCl3) δ = 2.45 (s, 3H), 6.60 (dd, J = 1.6, 4.4 Hz, 1H), 6.77-6.84 (m, 10H), 7.00 (d, J = 4.0 Hz, 1H), 7.08 (s, 1H), 7.12-7.21 (m, 8H), 7.29-7.32 (m, 4H), 7.45 (d, J = 8.0 Hz, 2H), 7.96 (s, 1H). 13C NMR (100 MHz, CDCl3) δ = 21.6, 121.9, 125.3, 125.4, 126.3, 126.4, 126.57, 126.64, 126.7, 127.7, 129.3, 129.4, 130.7, 131.1, 131.2, 131.4, 131.8, 132.5, 133.2, 135.1, 135.6, 139.1, 140.1, 140.9, 141.6, 146.3, 148.8, 149.0. HRMS (ESI+): calcd. for C44H31BF2N2Na [M+Na]+: 659.2441, found: 659.2442. meso-(p-Tolyl)-tetra(p-tolyl)benzo[b]-fused BODIPY (3b). Purification via column chromatography on silica gel (petroleum ether/ethyl acetate/dichloromethane = 12/1/1, v/v/v) afforded the product 3b (41.3 mg) in 60% yield as a black purple solid with a greenish metallic lustre. M.p.: > 250 °C. 1H NMR (400 MHz, CDCl3) δ = 2.08 (d, J = 8.4 Hz, 6H), 2.28 (d, J = 14.0 Hz, 6H), 2.45 (s, 3H), 6.57 (d, J = 3.6 Hz, 1H), 6.63 (d, J = 7.2 Hz, 7H),


Page 12 of 28

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6.94-7.04 (m, 7H), 7.08 (s, 1H), 7.16 (d, J = 7.6 Hz, 2H), 7.29 (d, J = 7.6 Hz, 2H), 7.44 (d, J = 8.0 Hz, 2H), 7.93 (s, 1H).

13

C NMR (100 MHz, CDCl3) δ = 21.2, 21.4, 21.60, 21.63,

121.5, 126.9, 127.0, 127.4, 128.4, 129.3, 129.5, 130.5, 130.9, 131.2, 131.6, 132.2, 132.7, 134.3, 134.4, 135.3, 135.6, 135.7, 136.0, 136.3, 137.3, 137.6 138.1, 139.3, 141.4, 147.1, 148.5, 148.6. HRMS (ESI+): calcd. for C48H39BF2N2Na [M+Na]+: 715.3067, found: 715.3064. meso-(p-Tolyl)-tetra(m-tolyl)benzo[b]-fused BODIPY (3c). Purification via column chromatography on silica gel (petroleum ether/ethyl acetate/dichloromethane = 12/1/1, v/v/v) afforded the product 3c (44.2 mg) in 64% yield as a black purple solid with a greenish metallic lustre. M.p.: 131-133 °C. 1H NMR (400 MHz, CDCl3) δ = 1.99-2.03 (m, 6H), 2.18 (s, 3H), 2.26 (d, J = 13.2 Hz, 3H), 2.45 (s, 3H), 6.55-6.74 (m, 9H), 6.91-7.16 (m, 10H), 7.29 (d, J = 8.0 Hz, 2H), 7.45 (d, J = 8.0 Hz, 2H), 7.97 (s, 1H). 13C NMR (100 MHz, CDCl3) δ = 21.2, 21.45, 21.48, 21.49, 21.6, 121.6, 125.8, 125.9, 126.88, 126.92, 126.94, 127.2, 127.4, 127.7, 129.2, 131.2, 131.6, 132.8, 135.2, 136.9, 139.1, 139.96, 139.98, 140.7, 141.5, 148.7. HRMS (ESI+): calcd. for C48H39BF2N2Na [M+Na]+: 715.3067, found: 715.3066. meso-(p-Tolyl)-tetra(p-methoxyphenyl)benzo[b]-fused BODIPY (3d). Purification via column chromatography on silica gel (petroleum ether/ethyl acetate/dichloromethane = 5/1/1, v/v/v) afforded the product 3d (41.0 mg) in 54% yield as a black purple solid with a greenish metallic lustre. M.p.: 174-177 °C. 1H NMR (400 MHz, DMSO-d6) δ = 2.42 (s, 3H), 3.53 (d, J = 6.4 Hz, 6H), 3.67 (s, 6H), 6.41 (dd, J = 8.4, 19.6 Hz, 4H), 6.61 (d, J = 8.4 Hz, 2H), 6.66-6.75 (m, 6H), 6.82-6.83 (m, 2H), 7.06 (dd, J = 8.4, 15.2 Hz, 4H), 7.14 (d, J = 4.4 Hz, 1H), 7.40 (d, J = 7.6 Hz, 2H), 7.57 (d, J = 7.6 Hz, 2H), 8.28 (s, 1H).

13

C NMR (100

MHz, DMSO-d6) δ = 26.5, 54.6, 54.8, 111.4, 111.7, 112.1, 113.1, 129.3, 130.6, 130.8, 131.1, 131.2, 131.6, 132.2, 133.2, 134.8, 141.5, 156.2, 156.5, 157.2, 157.7. HRMS (ESI+): calcd. for C48H39BF2N2NaO4 [M+Na]+: 779.2863, found: 779.2863. meso-(p-Tolyl)-tetra(p-fluorophenyl)benzo[b]-fused BODIPY (3e). Purification via



column chromatography on silica gel (petroleum ether/ethyl acetate/dichloromethane = 10/1/1, v/v/v) afforded the product 3e (57.2 mg) in 81% yield as a black purple solid with a greenish metallic lustre. M.p.: > 250 °C. 1H NMR (400 MHz, CDCl3) δ = 2.47 (s, 3H), 6.58 (q, J = 9.2 Hz, 4H), 6.65 (d, J = 4.4 Hz, 1H), 6.68-6.72 (m, 4H), 6.86-6.91 (m, 4H), 6.98 (s, 1H), 7.04-7.11 (m, 3H), 7.20-7.24 (m, 2H), 7.32 (d, J = 7.6 Hz, 2H), 7.44 (d, J = 8.0 Hz, 2H), 7.99 (s, 1H). 13C NMR (100 MHz, CDCl3) δ = 21.7, 110.2, 113.4, 113.6, 113.7, 113.9, 114.0, 114.2, 114.9, 115.1, 122.4, 125.3, 128.9, 129.4, 131.16, 131.21, 131.9, 132.0, 132.1, 132.4, 132.5, 133.0, 133.1, 133.76, 133.83, 134.1, 134.7, 134.8, 135.0, 135.75, 135.78, 136.57, 136.61, 138.1, 139.5, 141.9, 144.9, 146.3, 148.9, 149.8, 159.5, 159.7, 160.5, 160.7, 162.0, 162.1, 162.9, 163.2. HRMS (ESI+): calcd. for C44H27BF6N2Na [M+Na]+: 731.2064, found: 731.2064. meso-(p-Tolyl)-tetra(m-fluorophenyl)benzo[b]-fused BODIPY (3f). Purification via column chromatography on silica gel (petroleum ether/ethyl acetate/dichloromethane = 8/1/1, v/v/v) afforded the product 3f (40.1 mg) in 57% yield as a black purple solid with a greenish metallic lustre. M.p.: > 250 °C. 1H NMR (400 MHz, CDCl3) δ = 2.47 (s, 3H), 6.53-6.61 (m, 6H), 6.66 (d, J = 4.4 Hz, 1H), 6.85-6.93 (m, 6H), 6.99 (s, 1H), 7.06-7.07 (m, 3H), 7.12-7.18 (m, 2H), 7.33 (d, J = 7.6 Hz, 2H), 7.45 (d, J = 8.0 Hz, 2H), 8.02 (s, 1H). 13C NMR (100 MHz, CDCl3) δ = 21.7, 110.2, 112.77, 112.79, 112.80, 122.4, 122.65, 122.66, 122.68, 124.8, 124.9, 126.26, 126.29, 126.89, 126.92, 127.40, 127.43, 128.13, 128.15, 128.5, 129.4, 129.47, 129.51, 130.2, 131.1, 131.2, 131.5, 133.3, 134.1, 134.6, 138.1, 138.3, 139.66, 139.69, 140.7, 140.75, 140.78, 141.6, 141.7, 142.0, 142.25, 142.26, 142.33, 143.42, 143.44, 143.45, 149.0, 150.4, 161.1, 163.6. HRMS (ESI+): calcd. for C44H27BF6N2Na [M+Na]+: 731.2064, found: 731.2065. meso-(p-Tolyl)-tetra(p-chlorophenyl)benzo[b]-fused BODIPY (3g). Purification via column chromatography on silica gel (petroleum ether/ethyl acetate/dichloromethane = 10/1/1, v/v/v) afforded the product 3g (37.8 mg) in 49% yield as a black purple solid with a


Page 14 of 28

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greenish metallic lustre. M.p.: > 250 °C. 1H NMR (400 MHz, CDCl3) δ = 2.48 (s, 3H), 6.67 (dd, J = 1.6, 8.0 Hz, 5H), 6.87 (t, J = 8.8 Hz, 4H), 6.96 (s, 1H), 7.03-7.06 (m, 3H), 7.16-7.18 (m, 6H), 7.33 (d, J = 8.0 Hz, 2H), 7.43 (d, J = 8.0 Hz, 2H), 8.00 (s, 1H).

13

C

NMR (100 MHz, CDCl3) δ = 21.7, 122.7, 124.9, 126.9, 127.2, 127.5, 128.3, 128.7, 129.5, 131.11, 131.13, 131.7, 131.8, 132.0, 132.2, 132.8, 132.9, 133.0, 133.45, 133.49, 134.0, 134.7, 137.1, 138.0, 138.8, 142.0, 143.9, 149.0, 150.2. HRMS (ESI+): calcd. for C44H27BCl4F2N2Na [M+Na]+: 795.0882, found: 795.0881. meso-(p-Tolyl)-tetra(p-bromophenyl)benzo[b]-fused BODIPY (3h). Purification via column chromatography on silica gel (petroleum ether/ethyl acetate/dichloromethane = 10/1/1, v/v/v) afforded the product 3h (30.5 mg) in 32% yield as a black purple solid with a greenish metallic lustre. M.p.: > 250 °C. 1H NMR (400 MHz, CDCl3) δ = 2.48 (s, 3H), 6.60-6.67 (m, 5H), 6.95-7.12 (m, 10H), 7.33 (d, J = 8.0 Hz, 6H), 7.43 (d, J = 8.0 Hz, 2H), 8.00 (s, 1H).

13

C NMR (100 MHz, CDCl3) δ = 21.7, 110.2, 120.2, 120.3, 121.3, 122.7,

124.76, 124.80 128.6, 129.5, 129.8, 130.1, 130.5, 131.10, 131.13, 131.3, 132.1, 132.5, 133.2, 133.3, 133.8, 134.1, 134.7, 137.6, 138.5, 139.2, 139.6, 142.0, 143.7, 149.0, 150.3. HRMS (ESI+): calcd. for C44H27BBr4F2N2Na [M+Na]+: 970.8861, found: 970.8854. meso-(p-Tolyl)-tetra(m-(methoxycarbonyl)phenyl)benzo[b]-fused Purification

via

column

chromatography

on

silica

gel

BODIPY

(petroleum

(3i).

ether/ethyl

acetate/dichloromethane = 6/1/1, v/v/v) afforded the product 3i (33.2 mg) in 38% yield as a black purple solid with a greenish metallic lustre. M.p.: 181-182 °C. 1H NMR (400 MHz, CDCl3) δ = 2.45 (s, 3H), 3.75-3.79 (m, 6H), 3.86 (s, 6H), 6.64 (d, J = 4.4 Hz, 1H), 6.87-6.94 (m, 3H), 6.97 (s, 1H), 7.01-7.06 (m, 2H), 7.21-7.25 (m, 2H), 7.30 (d, J = 8.0 Hz, 3H), 7.44-7.57 (m, 7H), 7.80-7.85 (m, 2H), 7.92 (s, 1H), 7.96 (s, 1H).

13

C NMR (100 MHz,

CDCl3) δ = 21.7, 51.99, 52.04, 52.2, 122.5, 124.9, 127.1, 128.1, 128.3, 128.9, 129.4, 129.9, 131.2, 131.3, 133.8, 134.0, 138.9, 139.7, 141.9, 144.2, 149.0, 150.2, 166.9. HRMS (ESI+): calcd. for C52H39BF2N2NaO8 [M+Na]+: 891.2660, found: 891.2660.



meso-(p-Tolyl)-tetra(naphthalen-2-yl)benzo[b]-fused BODIPY (3j). Purification via column chromatography on silica gel (petroleum ether/ethyl acetate/dichloromethane = 12/1/1, v/v/v) afforded the product 3j (44.7 mg) in 53% yield as a black purple solid with a greenish metallic lustre. M.p.: > 250 °C. 1H NMR (400 MHz, CDCl3) δ = 2.39 (s, 3H), 6.54 (s, 1H), 6.99-7.12 (m, 10H), 7.37-7.80 (m, 26H).

13

C NMR (100 MHz, CDCl3) δ = 21.6,

121.9, 125.10, 125.15, 125.19, 125.24, 125.8, 125.9, 126.2, 127.3, 127.4, 127.60, 127.65, 127.66, 127.69, 127.74, 127.8, 128.1, 128.74, 128.75, 129.4, 131.1, 132.1, 132.3, 132.7, 133.0, 133.2, 137.9, 138.5, 141.6, 149.4. HRMS (ESI+): calcd. for C60H39BF2N2Na [M+Na]+: 859.3067, found: 859.3069. meso-(p-Tolyl)-tetra(methoxycarbonyl)benzo[b]-fused BODIPY (3k). Purification via column chromatography on silica gel (petroleum ether/ethyl acetate/dichloromethane = 4/1/1, v/v/v) afforded the product 3k (32.3 mg) in 57% yield as a black purple solid with a greenish metallic lustre. M.p.: 179-180 °C. 1H NMR (400 MHz, CDCl3) δ = 2.49 (s, 3H), 3.71 (s, 3H), 3.77 (s, 3H), 3.83 (s, 3H), 3.99 (s, 3H), 6.69 (d, J = 2.8 Hz, 1H), 6.95 (s, 2H), 7.09 (d, J = 4.0 Hz, 1H), 7.36 (d, J = 8.0 Hz, 2H), 7.47 (d, J = 7.6 Hz, 2H), 8.18 (s, 1H). 13C NMR (100 MHz, CDCl3) δ = 21.7, 52.8, 53.1, 54.1, 54.2, 129.7, 130.0, 130.5, 130.8, 133.8, 139.7, 142.3, 148.3, 148.9, 161.8, 164.1, 164.2, 165.2. HRMS (ESI+): calcd. for C28H23BF2N2NaO8 [M+Na]+: 587.1408, found: 587.1409. meso-Phenyl-tetraphenylbenzo[b]-fused BODIPY (4a). Purification via column chromatography on silica gel (petroleum ether/ethyl acetate/dichloromethane = 12/1/1, v/v/v) afforded the product 4a (50.2 mg) in 81% yield as a black purple solid with a greenish metallic lustre. M.p.: > 250 °C. 1H NMR (400 MHz, CDCl3) δ = 6.61 (d, J = 4.4 Hz, 1H), 6.77-6.82 (m, 10H), 6.98 (d, J = 4.0 Hz, 1H), 7.04 (s, 1H), 7.11-7.19 (m, 8H), 7.32 (d, J = 6.4 Hz, 2H), 7.48-7.58 (m, 5H), 7.98 (s, 1H). 13C NMR (100 MHz, CDCl3) δ = 110.2, 122.1, 125.3, 125.5, 126.3, 126.4, 126.5, 126.6, 126.7, 126.8, 127.7, 128.5, 129.4, 129.5, 130.6, 130.9, 131.06, 131.12, 131.8, 132.5, 133.2, 134.2, 135.2, 135.7, 139.1, 140.1, 140.9, 146.5,


Page 16 of 28

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148.4, 149.4. HRMS (ESI+): calcd. for C43H29BF2N2Na [M+Na]+: 645.2284, found: 645.2281. meso-(p-Methoxyphenyl)-tetraphenylbenzo[b]-fused BODIPY (4b). Purification via column chromatography on silica gel (petroleum ether/ethyl acetate/dichloromethane = 12/1/1, v/v/v) afforded the product 4b (53.7 mg) in 82% yield as a black purple solid with a greenish metallic lustre. M.p.: > 250 °C. 1H NMR (400 MHz, CDCl3) δ = 3.89 (s, 3H), 6.60-6.61 (m, 1H), 6.78-6.84 (m, 11H), 7.01-7.03 (m, 4H), 7.08 (s, 1H), 7.13-7.20 (m, 8H), 7.32 (d, J = 6.4 Hz, 2H), 7.52 (d, J = 8.8 Hz, 2H), 7.95 (s, 1H). 13C NMR (100 MHz, CDCl3) δ = 55.7, 114.2, 121.74, 121.75, 125.3, 125.4, 126.3, 126.4, 126.6, 126.66, 126.73, 126.8, 127.7, 129.5, 130.7, 131.2, 131.8, 132.5, 133.0, 133.1, 135.1, 135.6, 137.6, 138.3, 139.2, 139.5, 140.1, 140.9, 146.1, 148.5, 148.6, 162.3. HRMS (ESI+): calcd. for C44H31BF2N2NaO [M+Na]+: 675.2390, found: 675.2386. meso-(p-Dodecyloxyphenyl)-tetraphenylbenzo[b]-fused BODIPY (4c). Purification via column chromatography on silica gel (petroleum ether/ethyl acetate/dichloromethane = 12/1/1, v/v/v) afforded the product 4c (42.3 mg) in 52% yield as a black purple solid with a greenish metallic lustre. M.p.: 101-102 °C. 1H NMR (400 MHz, CDCl3) δ = 1.26-1.28 (m, 25H), 6.60 (dd, J = 2.0 Hz, 4.4, 1H), 6.76-6.86 (m, 10H), 7.00-7.03 (m, 4H), 7.09 (s, 1H), 7.17-7.19 (m, 7H), 7.31 (d, J = 6.0 Hz, 2H), 7.50 (d, J = 8.8 Hz, 2H), 7.94 (s, 1H).

13

C

NMR (100 MHz, CDCl3) δ = 22.9, 26.2, 29.3, 29.51, 29.53, 29.73, 29.76, 29.80, 29.82, 29.9, 32.1, 68.5, 110.2, 114.60, 114.66, 125.3, 125.4, 126.3, 126.4, 126.6, 126.65, 126.73, 127.1, 127.7, 129.5, 130.7, 131.2, 131.8, 132.5, 133.0, 133.1. HRMS (ESI+): calcd. for C55H53BF2N2NaO [M+Na]+: 829.4111, found: 829.4106. meso-(p-Dimethylaminophenyl)-tetraphenylbenzo[b]-fused Purification

via

column

chromatography

on

silica

gel

BODIPY (petroleum

(4d). ether/ethyl

acetate/dichloromethane = 12/1/1, v/v/v) afforded the product 4d (41.8 mg) in 63% yield as a black purple solid with a greenish metallic lustre. M.p.: > 250 °C. 1H NMR (400 MHz,



Page 18 of 28

CDCl3) δ = 3.10 (s, 6H), 6.58-6.59 (m, 1H), 6.76-6.84 (m, 12H), 7.09-7.21 (m, 10H), 7.32 (d, J = 6.4 Hz, 2H), 7.53 (d, J = 9.2 Hz, 2H), 7.88 (s, 1H). 13C NMR (100 MHz, CDCl3) δ = 40.3, 111.7, 120.8, 122.4, 125.2, 125.3, 125.5, 126.2, 126.3, 126.45, 126.50, 126.7, 127.7, 129.5, 130.8, 131.3, 131.9, 132.3, 132.5, 134.0, 134.8, 135.2, 139.5, 140.4, 141.1, 145.2, 146.5, 152.8. HRMS (ESI+): calcd. for C45H34BF2N3Na [M+Na]+: 688.2706, found: 688.2702. meso-(p-tert-Butylphenyl)-tetraphenylbenzo[b]-fused BODIPY (4e). Purification via column chromatography on silica gel (petroleum ether/ethyl acetate/dichloromethane = 12/1/1, v/v/v) afforded the product 4e (51.4 mg) in 76% yield as a black purple solid with a greenish metallic lustre. M.p.: > 250 °C. 1H NMR (400 MHz, CDCl3) δ = 1.37 (d, J = 3.6 Hz, 9H), 6.59 (s, 1H), 6.81 (d, J = 14 Hz, 10H), 7.02 (s, 1H), 7.12-7.25 (m, 9H), 7.31-7.32 (d, J = 4.0 Hz,, 2H), 7.46-7.55 (m, 4H), 7.96 (s, 1H). 13C NMR (100 MHz, CDCl3) δ = 31.4, 35.2, 121.81, 121.84, 125.3, 125.4, 125.6, 126.3, 126.4, 126.6, 126.67, 126.74, 127.7, 129.5, 130.7, 131.15, 131.18, 131.4, 131.8, 132.5, 133.4, 135.1, 135.6, 137.9, 139.2, 140.1, 140.9, 146.2, 148.8, 149.0, 154.7. HRMS (ESI+): calcd. for C47H37BF2N2Na [M+Na]+: 701.2910, found: 701.2911. meso-Mesityl-tetraphenylbenzo[b]-fused BODIPY (4f). Purification via column chromatography on silica gel (petroleum ether/ethyl acetate/dichloromethane = 12/1/1, v/v/v) afforded the product 4f (37.8 mg) in 57% yield as a black purple solid with a greenish metallic lustre. M.p.: 176-177 °C. 1H NMR (400 MHz, CDCl3) δ = 2.10-2.12 (m, 6H), 2.33-2.37 (m, 3H), 6.53 (d, J = 4.0 Hz, 1H), 6.72-6.82 (m, 10H), 6.85 (s, 1H), 6.92 (s, 2H), 7.12-7.20 (m, 9H), 7.33 (d, J = 5.6 Hz, 2H), 7.95 (s, 1H). 13C NMR (100 MHz, CDCl3) δ = 20.3, 21.3, 22.9, 124.3, 125.3, 125.4, 126.3, 126.4, 126.6, 126.7, 127.7, 128.4, 129.4, 130.1, 130.7, 131.1, 131.8, 131.9, 132.5, 135.2, 136.6, 139.09, 139.12, 140.1, 140.9, 146.3, 149.7. HRMS (ESI+): calcd. for C46H35BF2N2Na [M+Na]+: 687.2754, found: 687.2756. meso-(3,5-Bis(trifluoromethyl)phenyl)-tetraphenylbenzo[b]-fused


BODIPY

(4g).

Page 19 of 28 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


Purification

via

column

chromatography

on

silica

gel

(petroleum

ether/ethyl

acetate/dichloromethane = 12/1/1, v/v/v) afforded the product 4g (60.5 mg) in 80% yield as a black purple solid with a greenish metallic lustre. M.p.: > 250 °C. 1H NMR (400 MHz, CDCl3) δ = 6.69 (dd, J = 1.2, 4.4 Hz, 1H), 6.77-6.90 (m, 11H), 6.92 (s, 1H), 7.17-7.20 (m, 8H), 7.30 (d, J = 5.6 Hz, 2H), 8.04 (d, J = 4.0 Hz, 3H), 8.07 (s, 1H). 13C NMR (100 MHz, CDCl3) δ = 123.35, 123.36, 123.38, 123.39, 125.6, 125.8, 126.5, 126.6, 126.83, 126.85, 127.0, 127.1, 127.9, 130.6, 130.9, 130.96, 130.98, 131.01, 131.04, 131.8, 132.2, 132.4, 132.46, 132.48, 135.8, 136.1, 136.2, 138.7, 139.7, 140.7, 143.4, 147.9, 151.0. HRMS (ESI+): calcd. for C45H27BF8N2Na [M+Na]+: 781.2032, found: 781.2034. meso-(p-Cyanophenyl)-tetraphenylbenzo[b]-fused BODIPY (4h). Purification via column chromatography on silica gel (petroleum ether/ethyl acetate/dichloromethane = 6/1/1, v/v/v) afforded the product 4h (49.3 mg) in 76% yield as a black purple solid with a greenish metallic lustre. M.p.: > 250 °C. 1H NMR (400 MHz, CDCl3) δ = 6.64 (dd, J = 1.2, 4.4 Hz, 1H), 6.76-6.87 (m, 11H), 6.89 (s, 1H), 7.12-7.22 (m, 8H), 7.30 (d, J = 5.6 Hz, 2H), 7.65 (d, J = 8.0 Hz, 2H), 7.80 (d, J = 8.4 Hz, 2H), 8.01 (s, 1H). 13C NMR (100 MHz, CDCl3) δ = 110.2, 114.7, 118.0, 122.9, 125.5, 125.6, 126.3, 126.4, 126.7, 126.8, 126.9, 127.8, 129.5, 130.5, 131.0, 131.4, 131.7, 132.3, 132.4, 132.5, 135.7, 135.9, 137.6, 137.9, 138.4, 138.8, 139.8, 140.6, 145.1, 147.4, 150.6. HRMS (ESI+): calcd. for C44H28BF2N3Na [M+Na]+: 670.2237, found: 670.2234. meso-(p-Nitrophenyl)-tetraphenylbenzo[b]-fused BODIPY (4i). Purification via column chromatography on silica gel (petroleum ether/ethyl acetate/dichloromethane = 6/1/1, v/v/v) afforded the product 4i (28.3 mg) in 42% yield as a black purple solid with a greenish metallic lustre. M.p.: > 250 °C. 1H NMR (400 MHz, CDCl3) δ = 6.65 (d, J = 4.4 Hz, 1H), 6.76-6.90 (m, 12H), 7.12-7.20 (m, 8H), 7.30 (d, J = 5.6 Hz, 2H), 7.72 (d, J = 8.8 Hz, 2H), 8.02 (s, 1H), 8.37 (d, J = 8.4 Hz, 2H).

13

C NMR (100 MHz, CDCl3) δ = 123.0,

123.8, 125.5, 125.6, 126.4, 126.5, 126.7, 126.8, 127.0, 127.9, 130.5, 131.0, 131.66, 131.70,



132.4, 135.7, 136.0, 138.69, 138.73, 139.7, 140.2, 140.6, 144.6, 147.5, 149.2, 150.7. HRMS (ESI+): calcd. for C43H28BF2N3NaO2 [M+Na]+: 690.2135, found: 690.2139. Cell Culture. HepG2 cells were hatched in DMEM (Dublecco’s modified Eagle’s Medium) supplemented with 10% (v/v) FBS (fetal bovine serum), 100 kU/L of penicillin, and 100 mg/L of streptomycin at 37 ºC in a humidified atmosphere containing 5% CO2. Confocal Imaging Experiments. For Confocal fluorescence images experiments, HepG2 cells were incubated with 5.0 μM of 3k, 4c or 4d in PBS (phosphate buffered solution) containing 1% DMSO for 15 min at 37 ºC. After incubation HepG2 cells were washed twice with PBS. The cells were observed with a Zeiss LSM 780 confocal laser scanning microscope. For subcellular co-localization experiments, live cells were incubated with 5 μM of 4c or 4d in a PBS containing 1% DMSO for 15 min at 37 ºC. After incubated live cells were washed twice with PBS and 1 μM LysoTracker® Deep Red or LysoTracker® Green DND-26 were added and incubated for an additional 30 min before imaging. The cells were observed with a Zeiss LSM 780 confocal laser scanning microscope. Cytotoxicity Assays. Cell counting Kit-8 (CCK-8) assays were performed to evaluate the cytotoxicity effect of 4c and 4d. HepG2 cells were incubated in a 96-well culture plates at a volume of 100 μL (1×104 cells/mL) for a stationary culture. This media were changed into fresh media with a final volume of 200 μL containing sample in the 2-fold down dilution series and then incubated for 24 h. Then 10 μL of CCK-8 solution was added to each well, incubated for an additional 1 h and then absorbance readings at a wavelength of 490 nm were taken on a spectrophotometer (Molecular Devices, Sunnyvale, USA). The cell viability was calculated by the following formula: (mean optical density (OD) in treated wells/mean OD in control wells) × 100%. SUPPORTING INFORMATION STATEMENT The Supporting Information is available free of charge on the ACS Publications website.


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Additional UV-vis and emission spectra, microscopy images, cytotoxicity graphs, copies of 1

H NMR and 13C NMR spectra of all new compounds.

X-ray data for BODIPY 3a in CIF format (CIF) AUTHOR INFORMATION Corresponding Author [email protected]. [email protected]. Notes The authors declare no competing financial interest. ACKNOWLEDGMENTS This work was financially supported by grants from the National NSF of China (Nos 21772133, 21672154 and 21432005) and the Comprehensive Training Platform of Specialized Laboratory, College of Chemistry, Sichuan University. REFERENCES (1) (a) Boens, N.; Leen, V.; Dehaen, W. Fluorescent Indicators Based on BODIPY. Chem. Soc. Rev. 2012, 41, 1130–1172. (b) Ni, Y.; Wu, J. Far-red and Near Infrared BODIPY Dyes: Synthesis and Applications for Fluorescent pH Probes and Bio-imaging. Org. Biomol. Chem. 2014, 12, 3774–3791. (c) Kowada, T.; Maeda, H.; Kikuchi, K. BODIPY-based Probes for the Fluorescence Imaging of Biomolecules in Living Cells. Chem. Soc. Rev. 2015, 44, 4953–4972. (2) Kamkaew, A.; Lim, S. H.; Lee, H. B.; Kiew, L. V.; Chung, L. Y.; Burgess, K. BODIPY Dyes in Photodynamic Therapy. Chem. Soc. Rev. 2013, 42, 77–88.



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Using

Fused BODIPYs - ACS Publications

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