Annulation of BODIPYs

Jul 6, 2018 - ... of BODIPYs with Alkynes to Access Unsymmetrical Benzo[b]-Fused BODIPYs: ... *E-mail: [email protected]., *E-mail: [email protected]...
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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. 2018.83:9538-9546. Downloaded from pubs.acs.org by ST FRANCIS XAVIER UNIV on 08/17/18. For personal use only.

Key Laboratory of Green Chemistry and Technology of Ministry of Education, College of Chemistry, Sichuan University, 29 Wangjiang Road, Chengdu 610064, P.R. China S Supporting Information *

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 cells, and low cytotoxicity. ODIPY 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, including high molar absorption coefficients and fluorescence quantum yields, narrow emission bandwidths, excitation wavelengths located in the visible light region, resistance toward self-aggregation, good solubility, chemical and photochemical stability and thus have attracted 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 (hetero)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 ringfused BODIPY scaffolds have proven to be very effective methods in altering the electronic spectroscopies (Scheme 1).10 In recent years, numerous 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 multi-step reactions, inaccessible synthetic precursors, or unavoidable prefunctionalization. From the viewpoint of efficiency and step economy, the transition metal-catalyzed

B

© 2018 American Chemical Society

Scheme 1. Selected Examples of BODIPY Derivatives

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 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). 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 reacReceived: May 17, 2018 Published: July 6, 2018 9538

DOI: 10.1021/acs.joc.8b01239 J. Org. Chem. 2018, 83, 9538−9546

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The Journal of Organic Chemistry Scheme 2. Synthesis of b Bond-Fused BODIPYs

confirmed by nuclear magnetic resonance (NMR) spectroscopy, high-resolution mass spectrometry (HRMS), and singlecrystal 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 a N2 atmosphere, affording the desired product (3a) in 80% yield (Table 1, entry 13). 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 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% yield.

tions.12f,15 Therefore, an initial investigation into the C−H functionalization/annulation of BODIPY (1a) with 1,2diphenylethyne (2a) was conducted using the Pd(OAc)2/ Ag2CO3 catalyst system. Delightedly, the annulation product (3a) fused at the α- and β-positions of the BODIPY core was obtained in 35% yield using benzoic acid as an additive and 1,3,5-trimethylbenzene as solvent at 120 °C for 12 h under a N2 atmosphere (Table 1, entry 1). The structure of 3a was

Table 1. Optimization of Pd-Catalyzed Direct C−H Functionalization/Annulation of 8-(p-Tolyl)-BODIPY with 1,2Diphenylethynea

entry

Pd source

oxidant

additive

solvent

temp. (°C)

yieldb (%)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19c 20d

Pd(OAc)2 PdCl2 Pd(TFA)2 Pd2(dba)3 Pd(PPh3)2Cl2 Pd(PhCN)2Cl2 Pd(PhCN)2Cl2 Pd(PhCN)2Cl2 Pd(PhCN)2Cl2 Pd(PhCN)2Cl2 Pd(PhCN)2Cl2 Pd(PhCN)2Cl2 Pd(PhCN)2Cl2 Pd(PhCN)2Cl2 Pd(PhCN)2Cl2 Pd(PhCN)2Cl2 Pd(PhCN)2Cl2 Pd(PhCN)2Cl2 Pd(PhCN)2Cl2 Pd(PhCN)2Cl2

Ag2CO3 Ag2CO3 Ag2CO3 Ag2CO3 Ag2CO3 Ag2CO3 Ag2O AgOAc AgOPiv AgOPiv AgOPiv AgOPiv AgOPiv AgOPiv AgOPiv AgOPiv AgOPiv AgOPiv AgOPiv AgOPiv

PhCOOH PhCOOH PhCOOH PhCOOH PhCOOH PhCOOH PhCOOH PhCOOH PhCOOH PivOH CsOPiv

mesitylene mesitylene mesitylene mesitylene mesitylene mesitylene mesitylene mesitylene mesitylene mesitylene mesitylene mesitylene DCE DMF toluene dioxane DCE DCE DCE DCE

120 120 120 120 120 120 120 120 120 120 120 120 120 120 120 120 140 100 120 120

35 22 N.D. trace trace 35 trace trace 40 32 33 52 80 N.D. 52. 57 63 50 80 50

a 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 °C for 12 h under a N2 atmosphere; mesitylene = 1,3,5-trimethylbenzene, PivOH = 2,2dimethylpropanoic acid, DCE = 1,2-dichloroethane, DMF = N,N-dimethylformamide, N.D. = no detection. bIsolated yields. cFor 24 h. dFor 8 h.

9539

DOI: 10.1021/acs.joc.8b01239 J. Org. Chem. 2018, 83, 9538−9546

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The Journal of Organic Chemistry Scheme 3. Scope of Alkynesa

Scheme 4. Scope of BODIPYsa

a

Reaction conditions: 1 (0.1 mmol), 2a (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 12 h under a N2 atmosphere. Isolated yields.

Scheme 5. Plausible Mechanism for Pd-Catalyzed Direct C− H Functionalization/Annulation of BODIPYs with Alkynes

a 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 12 h under a N2 atmosphere. Isolated yields.

Subsequently, the scope with respect to BODIPY derivatives was investigated (Scheme 4). BODIPYs with an electrondonating 4-methoxy, 4-dodecyloxy, 4-dimethylamino, 4-tertbutyl, 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 direct C−H functionalization/annulation with 1,2-diphenylethyne (2a), giving the corresponding products in moderate to good yields (Scheme 4, 4b−4i). The nitro group in particular, which could not be tolerated in many C−H activations, was compatible under this catalytic condition, delivering 4i in an acceptable yield. 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-yl palladium species IM1. The 2 (or 6)position of BODIPY is more electron-rich and thus more susceptible to electrophilic attack.12f Next, alkyne 2a inserts into the Pd−C bond of IM1 to produce vinylpalladium species

IM2. Subsequently, another molecular 2a inserts into the Pd− C bond of IM2 to afford the butadienyl palladium 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 9540

DOI: 10.1021/acs.joc.8b01239 J. Org. Chem. 2018, 83, 9538−9546

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The Journal of Organic Chemistry

luminescence, it did not exhibit the specificity of cell organelle localization. Given that the emission of 4c is very weak in solution but exhibits a bright fluorescent image in live cells (Figure 1A), we thus 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 at 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 cytotoxicities of BODIPYs 4c and 4d were assessed by cell viability assay. As shown in Figure S5, 4c and 4d did not exhibit distinct toxicity to cultured HepG2 cells in the concentration range of 0.625−10 μM, indicating the potential practicability in live cell imaging. In summary, we have developed a highly efficient palladiumcatalyzed 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 groups, which provide 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 emission in cells, and low cytotoxicity, which would be potential lysosome-targeted reagents.

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. 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), whereas multiply arylTable 2. Photophysical Properties of 1a, 3e, 3k, 4d, and 4g dye

λabs (nm)a

λem (nm)b

(Φf)c

Stokes shift (cm−1)

1a 3e 3k 4d 4g

499 529 590 518 543

520 662 614 622 638

0.01 250 °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). 13C 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 product 3h (30.5 mg) in 32% yield as a black purple solid with a greenish metallic luster. Mp >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). 13C 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 BODIPY (3i). Purification via column chromatography on silica gel (petroleum ether/ethyl acetate/dichloromethane = 6/1/1, v/v/v) afforded product 3i (33.2 mg) in 38% yield as a black purple solid with a greenish metallic luster. Mp 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). 13C 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

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,4adiaza-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 backfilled 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 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 product 3a (50.9 mg) in 80% yield as a black purple solid with a greenish metallic luster. Mp >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 product 3b (41.3 mg) in 60% yield as a black purple solid with a greenish metallic luster. Mp >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), 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). 13C 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 product 3c (44.2 mg) in 64% yield as a black purple solid with a greenish metallic luster. Mp 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 product 3d (41.0 mg) in 54% yield as a black purple solid with a greenish metallic luster. Mp 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). 13C 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. 9542

DOI: 10.1021/acs.joc.8b01239 J. Org. Chem. 2018, 83, 9538−9546

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The Journal of Organic Chemistry

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 product 4e (51.4 mg) in 76% yield as a black purple solid with a greenish metallic luster. Mp >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 product 4f (37.8 mg) in 57% yield as a black purple solid with a greenish metallic luster. Mp 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). Purification via column chromatography on silica gel (petroleum ether/ethyl acetate/dichloromethane = 12/1/1, v/v/ v) afforded product 4g (60.5 mg) in 80% yield as a black purple solid with a greenish metallic luster. Mp >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 product 4h (49.3 mg) in 76% yield as a black purple solid with a greenish metallic luster. Mp >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 product 4i (28.3 mg) in 42% yield as a black purple solid with a greenish metallic luster. Mp >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). 13C 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 Dulbecco’s modified Eagle’s medium (DMEM) supplemented with 10% (v/v) fetal bovine serum (FBS), 100 kU/L of penicillin, and 100 mg/L of streptomycin at 37 °C in a humidified atmosphere containing 5% CO2.

ether/ethyl acetate/dichloromethane = 12/1/1, v/v/v) afforded product 3j (44.7 mg) in 53% yield as a black purple solid with a greenish metallic luster. Mp >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 product 3k (32.3 mg) in 57% yield as a black purple solid with a greenish metallic luster. Mp 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). 13 C 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 product 4a (50.2 mg) in 81% yield as a black purple solid with a greenish metallic luster. Mp > 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, 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 product 4b (53.7 mg) in 82% yield as a black purple solid with a greenish metallic luster. Mp >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 product 4c (42.3 mg) in 52% yield as a black purple solid with a greenish metallic luster. Mp 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). 13C 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 BODIPY (4d). Purification via column chromatography on silica gel (petroleum ether/ethyl acetate/dichloromethane = 12/1/1, v/v/v) afforded product 4d (41.8 mg) in 63% yield as a black purple solid with a greenish metallic luster. Mp >250 °C. 1H NMR (400 MHz, 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, 9543

DOI: 10.1021/acs.joc.8b01239 J. Org. Chem. 2018, 83, 9538−9546

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The Journal of Organic Chemistry Confocal Imaging Experiments. For confocal fluorescence image experiments, HepG2 cells were incubated with 5.0 μM 3k, 4c, or 4d in phosphate-buffered solution (FBS) containing 1% DMSO for 15 min at 37 °C. After incubation, HepG2 cells were washed twice with PBS. The cells were observed with a Zeiss LSM 780 confocal laser scanning microscope. For subcellular colocalization experiments, live cells were incubated with 5 μM 4c or 4d in PBS containing 1% DMSO for 15 min at 37 °C. After incubation, 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 effects of 4c and 4d. HepG2 cells were incubated in 96-well culture plates at a volume of 100 μL (1 × 104 cells/mL) for a stationary culture. These 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 and 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%.

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ASSOCIATED CONTENT

* Supporting Information S

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.8b01239. Additional UV−vis and emission spectra, microscopy images, cytotoxicity graphs, and copies of 1H and 13C NMR spectra of all new compounds (PDF) X-ray data for BODIPY 3a (CIF)

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Jingbo Lan: 0000-0001-5937-0987 Jingsong You: 0000-0002-0493-2388 Notes

The authors declare no competing financial interest.

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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.

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REFERENCES

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DOI: 10.1021/acs.joc.8b01239 J. Org. Chem. 2018, 83, 9538−9546

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DOI: 10.1021/acs.joc.8b01239 J. Org. Chem. 2018, 83, 9538−9546