Functionalized bispyridoneannelated BODIPY - Bright

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Nov 27, 2014 - Dipyrromethane 10 is a stable compound and quantitatively returns into dipyrromethene form after treatment with acid. The dipyrromethanes' ...
Dyes and Pigments 114 (2015) 215e221

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Functionalized bispyridoneannelated BODIPY e Bright long-wavelength fluorophores Yuriy V. Zatsikha, Viktor P. Yakubovskyi, Mykola P. Shandura, Yuriy P. Kovtun* Institute of Organic Chemistry, National Academy of Sciences of Ukraine, 5 Murmanska Str., 02094 Kyiv, Ukraine

a r t i c l e i n f o

a b s t r a c t

Article history: Received 15 October 2014 Received in revised form 17 November 2014 Accepted 19 November 2014 Available online 27 November 2014

A simple approach to the modification of BODIPY nucleus has been developed. The method is based on the reaction of monofunсtionalized acetaldehyde-substituted dye with primary amines or anilines followed by cyclization of enamine intermediates. This procedure allowed preparing a series of new stable intensive long-wavelength BODIPY derivatives (lem ¼ 680e720 nm) with two functional substituents useful for various practical purposes, including bioconjugation and other biomedical applications. © 2014 Published by Elsevier Ltd.

Keywords: BODIPY Long-wavelength dyes Fluorophore Functionalization Pyridone Annelation

1. Introduction Dyes derived from boron dipyrromethene (4,4-difluoro-4-bora3a,4a-diaza-s-indacene, BODIPY, BDP) have been attracting considerable attention over the past two decades. The everincreasing interest in this type of very important compounds stems from their excellent thermal, chemical, and photochemical stability, high molar absorption coefficients, high fluorescence quantum yields, general insensitivity to both solvent polarity and pH, large two-photon cross-section for multiphoton excitation, the lack of ionic charge, a good solubility, etc [1]. Often the dyes which will be used need to be appropriately functionalized (with the carboxyl, amino, azido groups, etc.). We have recently found a new approach to this problem via monopyridoneannelated compounds of type 1 [2]. In this case, the series of luminophores (lem ¼ 615 nm) with functional substituents useful for various practical purposes, including bioconjugation and other biomedical applications, can be readily obtained. Moreover, symmetrical bispyridoneannelated dye of type 7 emitting at the region of so-called “phototherapeutic window” (R ¼ i-Am, lem ¼ 683 nm) was synthesized too [3]. Compounds of this family are intensive long-wavelength dyes and from this point of view are of interest for various applications

* Corresponding author. E-mail address: [email protected] (Y.P. Kovtun). http://dx.doi.org/10.1016/j.dyepig.2014.11.016 0143-7208/© 2014 Published by Elsevier Ltd.

ranging from materials science to biology and medicine [1h,1i,4]. Thus, the goal of current research was to develop the convenient method of preparation of unsymmetrical dyes 7 with two different practically important substituents. This approach could lay the foundation for a new combinatorial strategy in the family of longwavelength BODIPY dyes, which is now considered to be of great importance in fluorescent probe development [5]. 2. Results and discussion' In order to achieve the goal the recently described BODIPY 2 [6] was used as a starting material (Scheme 1). The N-butyl-substituted compound was chosen due to its optimal solubility. Some characteristics of this aldehyde are similar to observed ones in the case of simpler analogs [7]. For example, formation of enamine 4 occurs by the reaction with tertiary amines. This time we have managed to isolate intermediate compound 3 which is enough stable to be characterized. While heating, especially with excess of amine, the Hofmann-type decomposition with ethylene evolution is easily observed. Quite expectedly, pericondensed heterocyclic system 5 was obtained after the treatment of compound 2 with boron trifluoride etherate solution. On the other hand, high reactivity of aldehyde 2 also leads to undesirable side processes, such as self-condensation or deformylation. In order to minimize these processes during the synthesis of enamines 6 the acetic acid should be added and the excess of amine

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Scheme 1. Chemical properties of aldehyde 2.

should be avoided. However, this is not enough to stop the reaction at enamine stage in all cases, as a further cyclization into pyridone derivatives 7 occurs, especially in the case of electron donating substituents. Since the non-fluorescent intermediates 6 were not of our interest, the reaction mixture was left for a few hours at room temperature to finish the reaction. In order to synthesize compound 7a (R ¼ H) ammonium acetate in ethanol was used. At the same time, the reaction with amines, which contain electron-withdrawing substituents (for example, allylamine or propargylamine) did not proceed so readily. That is why, the modification of the basic method which will include the use of enamine 8 [6] as a staring compound was developed (Scheme 2). This compound is essentially less reactive than appropriate aldehyde, therefore the time of reaction was longer e about 24 h in acetonitrile with significant excess of amine (4 equivalents). The reaction was carried out at room temperature, because the heating, especially higher than 60  C, facilitates the side processes more substantially. Thus, dyes 7h and 7i were synthesized in about 80% yield. The advantage of this method is that enamine 8 is a precursor of aldehyde 2, i.e. more available compound. Moreover, in this case it is very convenient to monitor visually the end of reaction as the reaction mass becomes colorless due to adduct 10 formation. Dipyrromethane 10 is a stable compound and quantitatively returns into dipyrromethene form after treatment with acid. The dipyrromethanes' salt-like forms were firstly described by the founder of BODIPY chemistry Alfred Treibs [8]. We have also observed the formation of such compounds earlier [2]. However, this process was possible only in the presence of alkali. Due to the electron-withdrawing influence of two annelated pyridone rings in the compounds of type 7, the nucleophilic attack at the meso-

position of dye is considerably facilitated, and can occur even after the treatment with amines. Anilides 11 are formed by the reaction of aldehyde 2 with anilines or aminoheterocycles. In contrast to enamines 6, they are stable compounds. Their cyclization into the compounds 12 require more severe conditions, namely continued refluxing in acetonitrile in the presence of sodium acetate (Scheme 3). It should be noted, that attempts to cyclize monoanilide derivatives of BODIPY of this range were unsuccessful [2]. Obtained bispyridoneannelated dyes 7aei and 12aeg have intensive absorption at 650e660 nm and fluorescence at 670e680 nm with high quantum yields (~70%, Table 1). Obviously, in terms of the brightness it is one of the highest result for this spectral region [4]. The dyes can be used in diverse applications, depending on the introduced substituent. For example, BODIPY dye 7e containing a hydrophobic decyl group is well soluble in hexane, so presumably it should be well soluble in lipid systems and thus useful for cell membrane studies. Compound 7g is functionalized with carboxyalkyl group suitable for bioconjugation reactions, e.g. for the fluorescent labeling of peptides, proteins and other aminecontaining biomolecules via the formation of amide bond. Dyes 7f,i are modified with azide and acetylene function, respectively, to be used as reagents in “click chemistry”. Alkene fragment was introduced into compound 7h e either for polymerization or further modification of the dye via the oxidation of ethylene bond. Arylsubstituted derivatives 12 possess similar spectroscopic properties to alkylsubstituted ones. However, in the case of anilides 11, some unexpected effects are observed. Due to PET process, free conjugated terminal amino groups in BODIPY most often lead to fluorescence quenching [9]. This takes place with enamines 6, but

Scheme 2. Synthesis of compounds 7h,i via enamine 8.

Scheme 3. Synthesis of anilinosubstituted dyes 11e12aeg.

Y.V. Zatsikha et al. / Dyes and Pigments 114 (2015) 215e221 Table 1 Optical properties of dyes obtained in CH2Cl2. Compound

labs nm(3105, m1 cm1)

Fwhma, cm1

lem nm (Ff, %)

3 4 5 7a 7b 7c 7d 7e

564(0.37) 654(0.58) 642(0.65) 651(1.16) 658(1.26) 656(1.30) 658(1.30) 659(0.98) 657(1.13)b 655(1.33) 658(1.09) 656(1.31) 654(1.22) 675(0.87) 682(0.68) 682(0.69) 667(0.80) 671(0.87) 672(0.83) 658(0.80) 657(0.90) 658(0.90) 658(1.17) 654(1.23) 653(1.23) 653(1.33) 654(1.11)

2693 2403 2131 1069 1422 1145 1131 1119 698 1404 1826 1812 1757 4233 4256 4333 2624 2854 2314 2622 1444 1420 1409 1761 1782 1795 1362

e 706c 677(62) 675(75) 683(74) 683(69) 683(68) 683(67) 676(51)b 681(71) 682(62) 681(70) 679(68) 718(31) 751c 758c 704(43) 708(47) 702(37) 697(56) 681(71) 683(70) 683(69) 678(66) 678(65) 678(70) 678(71)

7f 7g 7h 7i 11a 11b 11c 11d 11e 11f 11g 12a 12b 12c 12d 12e 12f 12g a b c

Fwhm ¼ full width at half-maximum height. In hexane. Fluoresce or quantum yield is too weak to be detected.

not with anilide 11a, which is quite intensive luminophore (Ff ¼ 31%). There are known few cases when relatively strong fluorescence persists in spite of the mentioned quenching effect [10]. In particular, this was observed by us in some anilidovinyl derivatives of BODIPY, but with significantly lower quantum yields [3,7]. Since compounds 11 are much deeper colored compared to cyclic analogues 12, it was of interest to investigate them in more detail. It was found that electron-donating substituents dramatically decrease the fluorescence, that is why only the emission maxima for the compounds 11b,c were detected. On the contrary, electron-withdrawing substituents (compounds 11deg) provide an opportunity to get sufficiently intensive fluorescence in the region at 700e720 nm. 3. Conclusions In summary, starting from monosubstituted dye 2 we have developed a very simple synthetic procedure that allows an efficient introduction of functional substituents into BODIPY core using aliphatic amines or anilines. The functionalized dyes containing alkyl, carboxyalkyl, azide, acetylene and other groups have been obtained. The prepared stable dyes are bright fluorophores with emission maximum in the region at 680 nm. Up to date the most popular fluorophores for this spectral region are substituted and modified indodicarbocyanines. Concerning the spectral characteristics, the obtained dyes are at least not worse. These dyes can be used e.g in biomedical research for the fluorescent labeling of biomolecules via the amide bond formation or click reactions, membrane studies, etc. In this case, in order to demonstrate the method's potential all studies were carried out with N-butyl starting material, but it should be specially noted that the abovedescribed general method allows the preparation of unsymmetrical BODIPY derivatives with different substituents at N-atoms of both pyridone rings. We believe that this approach lays the foundation for a new combinatorial strategy in the family of BODIPY

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dyes. In addition, it was found that anilides 11 with EWG are intensive luminophores in spectrum region at 700e720 nm. The above-described reactions illustrate well a new possibility for bifunctionalization of the long-wavelength BODIPY nucleus. 4. Experimental section Absorption spectra were recorded on a Shimadzu UV-2600 UVeVisible spectrophotometer. 1H NMR (500 MHz, 25  C, TMS as internal standard) spectra were recorded on a Bruker Avance 500 instrument. Chromato e mass spectrometry measurements were performed with LC/MS system consisting of Agilent 1100 Series HPLC instrument equipped with a diode matrix detector, and Agilent LC/MSD SL mass detector. APCI (Atmospheric Pressure Chemical Ionization) technique with detection of positive ions was used. Fluorescence spectra were recorded on a Solar CM 2203 fluorescence spectrophotometer. The relative fluorescent quantum yields (Ff) were determined using indodicarbocyanine iodide (Ff ¼ 0.25, EtOH) as the reference [11]. 4.1. Triethylammonium 2-carbethoxy-1,9-diphenyl-4,4-difluoro3a,4a,7-triaza-4-bora-cyclopenta[b]fuoren-8-on-3-(2-oxiethenyl) (3) To the solution of compound 2 (200 mg, 0.344 mmol) in toluene (10 mL) triethylamine (173 mg, 1.72 mmol) was added. The solution was stirred for 5 min at room temperature. The precipitate was filtered as a brown solid (214 mg, 90%). Mp ¼ 140 e 142  С; 1H NMR (500 MHz, DMSO-d6.): dH 9.43 (d, J ¼ 8.9 Hz, 1H), 8.84 (bs, 1H), 7.50e7.13 (m, 11H), 6.59 (d, J ¼ 7.1 Hz, 1H), 6.09 (s, 1H), 5.89 (d, J ¼ 8.1 Hz, 1H), 4.16e4.06 (m, 2H), 3.87 (t, J ¼ 7.3 Hz, 2H), 3.08 (q, J ¼ 6.6 Hz, 6H), 1.65e1.54 (m, 2H), 1.35e1.23 (m, 2H), 1.16 (t, J ¼ 7.3 Hz, 9H), 1.09e1.02 (m, 3H), 0.89 (t, J ¼ 7.3 Hz, 3H); LC-MS: m/z 582 ([M þ H]þ). Anal. calcd for C35H32BF2N3O5: C, 68.62; H, 6.64; N 8.21%. Found C, 68.83; H, 6.45; N, 8.14%. 4.2. 2-carbethoxy-3-[2-(diethylamino)ethenyl]-7-(1-butyl)-1,9diphenyl-4,4-difluoro-3a,4a,7-triaza-4-bora-cyclopenta [b] fluoren-8-on To the solution of compound 2 (200 mg, 0.344 mmol) in toluene (10 mL) triethylamine (173 mg, 1.72 mmol) was added. The solution was stirred for 12 h at room temperature. The solvent was evaporated to dryness and the resulting solid was purified by silica gel column chromatography using ethyl acetate e hexane (1:1, v/v) as eluent. The product was isolated as a cyan solid (164 mg, 74%). Mp ¼ 231e233  С; 1H NMR (500 MHz, DMSO-d6.): dH NMR (500 MHz) dH 8.35 (s, 1H), 7.57e7.43 (m, 6H), 7.44e7.33 (m, 4H), 7.32 (d, J ¼ 7.3 Hz, 1H), 6.61 (d, J ¼ 7.1 Hz), 6.48 (s, 1H), 6.19 (d, J ¼ 12.5 Hz, 1H), 4.11 (q, J ¼ 5.6 Hz, 2H), 3.89 (t, J ¼ 6.7 Hz, 2H), 3.62e3.50 (m, 4H), 1.65e1.56 (m, 2H), 1.37e1.21 (m, 8H), 0.96 (t, J ¼ 7.2 Hz, 3H), 0.90 (t, J ¼ 7.2 Hz, 3H); LC-MS: m/z 637 ([M þ H]þ). Anal. calcd for C37H39BF2N4O3: C, 69.81; H, 6.18; N 8.80%. Found C, 67.05; H, 6.02; N, 8.57%. 4.3. Compound 5 To the solution of compound 2 (200 mg, 0.344 mmol) in toluene (10 mL) boron trifluoride etherate (49 mg, 0.344 mmol) was added. The solution was stirred for 20 min at room temperature. The precipitate was filtered and purified by silica gel column chromatography using ethyl acetate e hexane (1:1, v/v) as eluent. The product was isolated as a cyan solid (156 mg, 81%). Mp 155e157 оС; 1 H NMR (500 MHz, DMSO-d6): dH 7.85e7.75 (m, 2H), 7.65e7.39 (m, 10H), 7.02 (s, 1H), 6.74 (d, J ¼ 7.3 Hz, 1H), 6.66 (d, J ¼ 5.1 Hz, 1H), 4.24e4.16 (m, 2H), 3.97e3.84 (m, 2H), 1.69e1.54 (m, 2H), 1.36e1.24 (m, 2H), 1.16 (t, J ¼ 6.5 Hz, 3H), 0.90 (t, J ¼ 6.5 Hz, 3H); LC-MS: m/z

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587 ([M þ H]þ). Anal. calcd for C34H32BFN3O4: C, 70.84; H, 5.60; N 7.29%. Found C, 70.97; H, 5.41; N, 7.18%. 4.4. 2-butyl-10,12-diphenyl-8-hydro-5,5-difluoro-2,4b,5a,8tetraaza-5-bora-indeno[2,1-b]fluorene-1,9-dione (7a) The mixture of compound 2 (250 mg, 0.43 mmol) and NH4OAc (132 mg, 1.72 mmol) in ethanol (10 mL) was refluxed for 3 min and left for a few hours at room temperature. The precipitate was filtered and washed with ethanol. The product isolated as a green solid (150 mg, 65%). Mp > 250  С; 1H NMR (500 MHz, DMSO-d6): dH 11.42 (d, J ¼ 6.6 Hz, 1H), 7.88 (d, J ¼ 7.6 Hz, 1H), 7.73 (m, 4H), 7.60e7.47 (m, 7H), 7.29 (s, 1H), 6.70e6.55 (m, 2H), 3.90 (t, J ¼ 7.2 Hz, 2H), 1.74e1.50 (m, 2H), 1.40e1.20 (m, 2H), 0.90 (t, J ¼ 6.8 Hz, 3H); LC-MS: m/z 535 ([M þ H]þ). Anal. calcd for C31H25BF2N4O2: C, 69.68; H, 4.72; N 10.48%. Found C, 69.96; H, 4.53; N, 10.26%. 4.5. General procedure for the synthesis of compounds 7beg To the solution of compound 3 (150 mg, 0.258 mmol) and acetic acid (77 mg, 1.29 mmol) in chloroform (5 mL) appropriate amine (0.31 mmol) was added. After 3 h the solution was washed with water, dried over Na2SO4 and evaporated to dryness. The precipitate was washed with hot ethanol (10 mL) and filtered. 4.6. 2,8-dibutyl-10,12-diphenyl-5,5-difluoro-2,4b,5a,8-tetraaza-5bora-indeno[2,1-b]fluorene-1,9-dione (7b) The product was isolated as a green solid (134 mg, 88%). Mp > 250  С; 1H NMR (500 MHz, CDCl3): dH 7.64e7.55 (m, 4H), 7.50e7.40 (m, 6H), 7.38 (s, 1H), 7.32 (d, J ¼ 7.4 Hz, 2H), 6.78 (d, J ¼ 7.3 Hz, 2H), 3.89 (t, J ¼ 7.3 Hz, 4H), 1.78e1.61 (m, 4H), 1.43e1.29 (m, 4H), 0.92 (t, J ¼ 7.3 Hz, 4H); LC-MS: m/z 591 ([M þ H]þ). Anal. calcd for C35H33BF2N4O2: C, 71.19; H, 5.63; N 9.49%. Found C, 71.50; H, 5.45; N, 9.25%.

product was isolated as a green solid (153 mg, 88%). Mp 242e244

оС; 1H NMR (500 MHz, CDCl ): d 7.62e7.57 (m, 4H), 7.50e7.42 (m, 3 H

6H), 7.38 (s, 1H), 7.32 (d, J ¼ 7.4 Hz, 2H), 6.78 (d, J ¼ 7.4 Hz, 2H), 3.91e3.85 (m, 4H), 1.73e1.65 (m, 4H), 1.42e1.17 (m, 16H), 0.92 (t, J ¼ 7.3 Hz, 3H), 0.85 (t, J ¼ 6.7 Hz, 3H); LC-MS: m/z 675 ([M þ H]þ). Anal. calcd for C41H45BF2N4O2: C, 72.99; H, 6.72; N 8.30%. Found C, 73.25; H, 6.62; N, 8.11%. 4.10. 2-butyl-10,12-diphenyl-8-(2-azidoethyl)-5,5-difluoro2,4b,5a,8-tetraaza-5-bora-indeno[2,1-b]fluorene-1,9-dione (7f) Time of stirring 5 h, 2-azidoethylamine diethyl etherate solution was used. The product was isolated as a green solid (180 mg, 86%). Mp > 250  С; 1H NMR (500 MHz, CDCl3): dH 7.63e7.56 (m, 4H), 7.50e7.38 (m, 7H), 7.34 (d, J ¼ 7.2 Hz, 1H), 6.82 (d, J ¼ 7.0 Hz, 1H), 6.78 (d, J ¼ 7.0 Hz, 1H), 4.05e4.00 (m, 2H), 3.89 (t, J ¼ 7.0 Hz, 2H) 3.70e3.65 (m, 2H), 1.74e1.64 (m, 2H), 1.42e1.30 (m, 2H), 0.92 (t, J ¼ 6.9 Hz, 3H); LC-MS: m/z 604 ([M þ H]þ). Anal. calcd for C33H28BF2N7O2: C, 65.68; H, 4.68; N 16.25%. Found C, 65.89; H, 4.45; N, 16.18%. 4.11. 2-butyl-10,12-diphenyl-8-(5-carboxypentyl)-5,5-difluoro2,4b,5a,8-tetraaza-5-bora-indeno[2,1-b]fluorene-1,9-dione (7g) Isopropanol was used as a solvent, time of stirring 4 h. The resulting solid was purified by silica gel column chromatography using ethyl acetate as eluent. The product was isolated as a brown solid (80 mg, 47.8%). Mp > 250  С; 1H NMR (500 MHz, DMSO-d6): dH 7.90 (d, J ¼ 7.1 Hz, 2H), 7.78e7.65 (m, 4H), 7.58e7.44 (m, 6H), 7.29 (s, 1H), 6.63 (d, J ¼ 7.7 Hz, 1H), 3.95e3.85 (m, 4H), 2.22 (t, J ¼ 6.6 Hz, 2H), 1.65e1.61 (m, 4H), 1.54e1.51 (m, 2H), 1.32e1.28 (m, 4H), 0.90 (t, J ¼ 7.4 Hz, 3H); LC-MS: m/z 649 ([M þ H]þ). Anal. calcd for C37H35BF2N4O4: C, 68.53; H, 5.44; N 8.64%. Found C, 68.81; H, 5.30; N, 8.40%. 4.12. General procedure for the synthesis of compounds 7h,i

4.7. 2-butyl-10,12-diphenyl-8-(2-hydroxyethyl)-5,5-difluoro2,4b,5a,8-tetraaza-5-bora-indeno[2,1-b]fluorene-1,9-dione (7c) The product was isolated as a green solid (138 mg, 93%). Mp > 250  С; 1H NMR (500 MHz, DMSO-d6): dH 7.89 (d, J ¼ 7.4 Hz, 1H), 7.81 (d, J ¼ 7.4 Hz, 1H), 7.77e7.67 (m, 4H), 7.57e7.44 (m, 6H), 7.28 (s, 1H), 6.69e6.57 (m, 2H), 4.92e4.90 (m, 1H) 3.97 (t, J ¼ 7.9 Hz, 2H), 3.90 (t, J ¼ 7.1 Hz, 2H), 3.69e3.58 (m, 2H), 1.69e1.56 (m, 2H), 1.37e1.23 (m, 2H), 0.90 (t, J ¼ 7.2 Hz, 3H); LC-MS: m/z 579 ([M þ H]þ). Anal. calcd for C33H29BF2N4O3: C, 68.52; H, 5.05; N 9.69%. Found C, 68.80; H, 4.91; N, 9.43%. 4.8. 2-butyl-10,12-diphenyl-8-(2-methoxyethyl)-5,5-difluoro2,4b,5a,8-tetraaza-5-bora-indeno[2,1-b]fluorene-1,9-dione (7d) The product was isolated as a green solid (137 mg, 90%). Mp > 250  С; 1H NMR (500 MHz, CDCl3): dH 7.64e7.55 (m, 4H), 7.48e7.40 (m, 7H), 7.38 (s, 1H), 7.32 (d, J ¼ 7.5 Hz, 1H), 6.83e6.72 (m, 2H), 4.08 (t, J ¼ 4.8 Hz, 2H), 3.89 (t, J ¼ 7.4 Hz, 2H), 3.61 (t, J ¼ 4.8 Hz, 2H), 3.31 (s, 3H), 1.75e1.63 (m, 2H), 1.42e1.30 (m, 2H), 0.92 (t, J ¼ 7.3 Hz, 3H); LC-MS: m/z 593 ([M þ H]þ). Anal. calcd for C34H31BF2N4O3: C, 68.93; H, 5.27; N 9.46%. Found C, 69.17; H, 5.16; N, 9.29%. 4.9. 2-butyl-10,12-diphenyl-8-decyl-5,5-difluoro-2,4b,5a,8tetraaza-5-bora-indeno[2,1-b]fluorene-1,9-dione (7e) The resulting solid was purified by silica gel column chromatography using ethyl acetate e hexane (1:3, v/v) as eluent. The

To the solution of compound 8 (100 mg, 0.164 mmol) in acetonitrile (10 mL) appropriate amine (0.657 mmol) was added. The solution was stirred for 24 h, to the resulting colorless mass acetic acid was added. The solution was diluted with water and dye was extracted with DCM. The solvent was evaporated to dryness and the resulting solid was purified by silica gel column chromatography using ethyl acetate e toluene (1:4, v/v) as eluent. 4.13. 2-butyl-10,12-diphenyl-8-(prop-1-en-3-yl)-5,5-difluoro2,4b,5a,8-tetraaza-5-bora-indeno[2,1-b]fluorene-1,9-dione (7h) The product was isolated as a green solid (75 mg, 80%). Mp > 250  С; 1H NMR (500 MHz, CDCl3): dH 7.47 (m, 1H), 7.34e7.30 (m, 2H), 6.81 (d, J ¼ 7.6 Hz, 1H), 6.78 (d, J ¼ 7.6 Hz, 1H), 5.98e5.85 (m, 1H), 5.28e5.18 (m, 2H), 4.54 (d, J ¼ 5.5 Hz, 2H), 3.89 (t, J ¼ 7.4 Hz, 2H), 1.74e1.64 (m, 2H), 1.42e1.30 (m, 2H), 0.92 (t, J ¼ 7.4 Hz, 3H); LC-MS: m/z 575 ([M þ H]þ). Anal. calcd for C34H29BF2N4O2: C, 71.09; H, 5.09; N 9.75%. Found C, 71.28; H, 4.90; N, 9.55%. 4.14. 2-butyl-10,12-diphenyl-8-(prop-1-yn-3-yl)-5,5-difluoro2,4b,5a,8-tetraaza-5-bora-indeno[2,1-b]fluorene-1,9-dione (7i) The product was isolated as a green solid (72 mg, 77%). Mp > 250  С; 1H NMR (500 MHz, CDCl3): dH 7.63e7.54 (m, 5H), 7.50e7.43 (m, 6H), 7.39 (s, 1H), 7.34 (d, J ¼ 7.3 Hz, 1H), 6.88 (d, J ¼ 7.3 Hz, 1H), 6.78 (d, J ¼ 7.3 Hz, 1H), 4.72 (s, 2H), 3.89 (t, J ¼ 7.1 Hz, 2H), 2.42 (s, 1H), 1.74e1.63 (m, 2H), 1.42e1.30 (m, 2H), 0.92 (t, J ¼ 7.1 Hz, 3H); LC-MS: m/z 673 ([M þ H]þ). Anal. calcd for

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219

C34H27BF2N4O2: C, 71.34; H, 4.75; N 9.79%. Found C, 71.65; H, 4.59; N, 9.70%.

C40H34BF5N4O3: C, 66.31; H, 4.73; N 7.73%. Found C, 66.58; H, 4.47; N, 7.57%.

4.15. General procedure for the synthesis of compounds 11aeg

4.20. 2-carbethoxy-3-[2-[(2-fluorophenyl)amino]ethenyl]-7-(1butyl)-1,9-diphenyl-4,4-difluoro-3a,4a,7-triaza-4-bora-cyclopenta [b] fluoren-8-on (11e)

The solution of compound 2 (300 mg, 0.516 mmol), acetic acid (62 mg, 1.03 mmol) and appropriate aniline derivative (0.61 mmol) in chloroform (20 mL) was stirred at room temperature for 1 h. The solution was washed with water, dried over Na2SO4 and evaporated to dryness. The resulting solid was purified by silica gel column chromatography using ethyl acetate e hexane (1:1, v/v) as eluent. 4.16. 2-carbethoxy-3-[2-(phenylamino)ethenyl]-7-(1-butyl)-1,9diphenyl-4,4-difluoro-3a,4a,7-triaza-4-bora-cyclopenta [b] fluoren8-on (11a) The product was isolated as a dark cyan solid (284 mg, 84%). Mp 249e251 оС; 1H NMR (500 MHz, CDCl3): dH 9.06 (t, J ¼ 13.3 Hz, 1H), 7.60 (d, J ¼ 13.3 Hz, 1H), 7.54 (d, J ¼ 7.1 Hz, 2H), 7.44e7.26 (m, 10H), 7.20 (d, J ¼ 7.4 Hz, 1H), 7.11e7.03 (m, 3H), 6.84 (s, 1H), 6.83e6.75 (m, 2H), 4.07 (q, J ¼ 7.2 Hz, 2H), 3.91 (t, J ¼ 7.2 Hz, 2H), 1.77e1.63 (m, 2H), 1.41e1.31 (m, 2H), 0.98e0.86 (m, 6H); LC-MS: m/z 657 ([M þ H]þ). Anal. calcd for C39H35BF2N4O3: C, 71.35; H, 5.37; N 8.53%. Found C, 71.56; H, 5.28; N, 8.37%. 4.17. 2-carbethoxy-3-[2-[(4-methoxyphenyl)amino]ethenyl]-7-(1butyl)-1,9-diphenyl-4,4-difluoro-3a,4a,7-triaza-4-bora-cyclopenta [b] fluoren-8-on (11b) The product was isolated as a dark cyan solid (155 mg, 44%). Mp 163e165 оС; 1H NMR (500 MHz, CDCl3): dH 8.96 (t, J ¼ 13.3 Hz, 1H), 7.65 (d, J ¼ 13.3 Hz, 1H), 7.53 (d, J ¼ 7.2 Hz, 2H), 7.46e7.21 (m, 10H), 7.17 (d, J ¼ 7.4 Hz, 1H), 7.01 (d, J ¼ 8.8 Hz, 2H), 6.88 (d, J ¼ 8.8 Hz, 2H), 6.83e6.76 (m, 2H), 6.72 (d, J ¼ 13.1 Hz, 1H), 4.04 (q, J ¼ 7.2 Hz, 2H), 3.91 (t, J ¼ 6.8 Hz, 2H), 3.78 (s, 3H), 1.79e1.60 (m, 3H), 1.45e1.30 (m, 2H), 0.97e0.82 (m, 6H); LC-MS: m/z 687 ([M þ H]þ). Anal. calcd for C40H37BF2N4O4: C, 69.98; H, 5.43; N 8.16%. Found C, 67.25; H, 5.20; N, 7.94%. 4.18. 2-carbethoxy-3-[2-[(4-ethoxyphenyl)amino]ethenyl]-7-(1butyl)-1,9-diphenyl-4,4-difluoro-3a,4a,7-triaza-4-bora-cyclopenta [b] fluoren-8-on (11c) The product was isolated as a dark cyan solid (173 mg, 48%). Mp 153e155 оС; 1H NMR (500 MHz, CDCl3): dH 8.96 (t, J ¼ 12.6 Hz, 1H), 7.67 (d, J ¼ 14.1 Hz, 1H), 7.53 (d, J ¼ 7.2 Hz, 2H), 7.42e7.22 (m, 8H), 7.17 (d, J ¼ 7.4 Hz, 1H), 6.98 (d, J ¼ 8.8 Hz, 2H), 6.86 (d, J ¼ 8.8 Hz, 2H), 6.82e6.77 (m, 2H), 6.72 (d, J ¼ 12.9 Hz, 1H), 4.08e3.96 (m, 4H), 3.91 (t, J ¼ 7.2 Hz, 2H), 1.73e1.64 (m, 2H), 1.43e1.31 (m, 5H), 0.93e0.85 (m, 6H); LC-MS: m/z 701 ([M þ H]þ). Anal. calcd for C41H39BF2N4O4: C, 70.29; H, 5.61; N 8.00%. Found C, 70.52; H, 5.49; N, 7.87%. 4.19. 2-carbethoxy-3-[2-[3-(trifluoromethyl)phenyl] aminoethenyl]-7-(1-butyl)-1,9-diphenyl-4,4-difluoro-3a,4a,7triaza-4-bora-cyclopenta [b] fluoren-8-on (11d) The resulting solid was purified by silica gel column chromatography using ethyl acetate e hexane (1:3, v/v) as eluent. The product was isolated as a dark cyan solid (249 mg, 67%). Mp 140e142 оС; 1H NMR (500 MHz, CDCl3): dH 9.00 (t, J ¼ 13.2 Hz, 1H), 7.85 (d, J ¼ 13.2 Hz, 1H), 7.53 (d, J ¼ 7.0 Hz, 2H), 7.47e7.13 (m, 14H), 6.88 (s, 1H), 6.85e6.73 (m, 2H), 4.05 (q, J ¼ 6.9 Hz, 2H), 3.91 (t, J ¼ 7.1 Hz, 2H), 1.76e1.62 (m, 2H), 1.41e1.27 (m, 2H), 0.89 (t, J ¼ 7.1 Hz, 6H); LC-MS: m/z 725 ([M þ H]þ). Anal. calcd for

The resulting solid was purified by silica gel column chromatography using ethyl acetate e hexane (1:2, v/v) as eluent. The product was isolated as a dark cyan solid (216 mg, 62%). Mp 143e145 оС; 1H NMR (500 MHz, CDCl3): dH 9.02 (t, J ¼ 13.4 Hz, 1H), 7.53 (d, J ¼ 6.9 Hz, 2H), 7.47e7.25 (m, 10H), 7.23e7.06 (m, 3H), 7.04e6.96 (m, 1H), 6.89 (s, 1H), 6.84 (d, J ¼ 13.4 Hz, 1H), 6.79 (d, J ¼ 7.1 Hz, 1H), 4.07 (q, J ¼ 7.2 Hz, 2H), 3.90 (t, J ¼ 7.2 Hz, 2H), 1.74e1.64 (m, 2H), 1.43e1.29 (m, 2H), 0.98e0.83 (m, 6H); LC-MS: m/ z 674 ([M þ H]þ). Anal. calcd for C39H34BF3N4O3: C, 69.44; H, 5.08; N 8.31%. Found C, 69.63; H, 4.93; N, 8.10%. 4.21. 2-carbethoxy-3-[2-[(4-nitrophenyl)amino]ethenyl]-7-(1butyl)-1,9-diphenyl-4,4-difluoro-3a,4a,7-triaza-4-bora-cyclopenta [b] fluoren-8-on (11f) The resulting solid was purified by silica gel column chromatography using ethyl acetate e hexane (1:2, v/v) as eluent. The product was isolated as a dark cyan solid (238 mg, 66%). Mp 185e187 оС; 1H NMR (500 MHz, CDCl3): dH 8.99 (t, J ¼ 12.9 Hz, 1H), 8.19 (d, J ¼ 8.9 Hz, 2H), 8.05 (d, J ¼ 9.1 Hz, 1H), 7.53 (d, J ¼ 6.9 Hz, 2H), 7.44e7.26 (m, 8H), 7.02 (d, J ¼ 9.0 Hz, 2H), 6.94 (s, 1H), 6.90 (d, J ¼ 13.7 Hz, 1H), 6.77 (d, J ¼ 6.8 Hz, 1H), 6.59 (d, J ¼ 9.0 Hz, 1H), 4.05 (q, J ¼ 7.0 Hz, 2H), 3.91 (t, J ¼ 6.7 Hz, 2H), 1.75e1.63 (m, 2H), 1.40e1.28 (m, 2H), 0.95e0.84 (m, 6H); LC-MS: m/z 702 ([M þ H]þ). Anal. calcd for C39H34BF2N5O5: C, 66.77; H, 4.89; N 9.98%. Found C, 66.92; H, 4.79; N, 9.88%. 4.22. 2-carbethoxy-3-[2-(pyridin-2-ylamino)ethenyl]-7-(1-butyl)1,9-diphenyl-4,4-difluoro-3a,4a,7-triaza-4-bora-cyclopenta [b] fluoren-8-on (11f) 2-aminopyridine was used as an amine. The product was isolated as a cyan solid (150 mg, 44%). Mp 181e183 оС; 1H NMR (500 MHz, CDCl3): dH 11.42 (d, J ¼ 11.2 Hz, 1H), 9.03 (t, J ¼ 12.4 Hz, 1H), 8.33 (d, J ¼ 4.4 Hz, 1H), 7.78 (t, J ¼ 6.9 Hz, 1H), 7.63 (d, J ¼ 7.4 Hz, 1H), 7.59e7.34 (m, 10H), 7.08 (t, J ¼ 6.9 Hz, 1H), 6.99 (d, J ¼ 8.1 Hz, 1H), 6.80e6.73 (m, 2H), 6.58 (d, J ¼ 7.0 Hz, 1H), 4.25 (q, J ¼ 7.1 Hz, 2H), 3.89 (t, J ¼ 7.2 Hz, 2H), 1.65e1.55 (m, 2H), 1.33e1.23 (m, 2H), 1.09 (t, J ¼ 7.1 Hz, 3H), 0.89 (t, J ¼ 7.4 Hz, 3H); LC-MS: m/z 658 ([M þ H]þ). Anal. calcd for C38H34BF2N5O3: C, 69.41; H, 5.21; N 10.65%. Found C, 69.70; H, 5.10; N, 10.43%. 4.23. General procedure for the synthesis of compounds 12a-g The solution of compound 11aeg (0.2 mmol), AcONa (17 mg, 0.2 mmol) in acetonitrile (10 mL) was refluxed for 5 h. The reaction mixture was cooled down, the solvent was evaporated to dryness and the resulting solid was purified by silica gel column chromatography using ethyl acetate e toluene (1:4, v/v) as eluent. 4.24. 2,10,12-triphenyl-8-(prop-1-en-3-yl)-5,5-difluoro-2,4b,5a,8tetraaza-5-bora-indeno[2,1-b]fluorene-1,9-dione (12a) The resulting solid was purified by silica gel column chromatography using ethyl acetate e toluene (1:6, v/v) as eluent. Time of refluxing e 24 h. The product was isolated as a green solid (115 mg, 73%). Mp > 250  С; 1H NMR (500 MHz, CDCl3): dH 7.67e7.55 (m, 4H), 7.49e7.30 (m, 13H), 6.91 (d, J ¼ 7.1 Hz, 1H), 6.79 (d, J ¼ 7.2 Hz,

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1H), 3.90 (t, J ¼ 7.2 Hz, 2H), 1.76e1.63 (m, 2H), 1.43e1.31 (m, 2H), 0.92 (t, J ¼ 7.2 Hz, 3H); LC-MS: m/z 611 ([M þ H]þ). Anal. calcd for C37H29BF2N4O2: C, 72.80; H, 4.79; N 9.18%. Found C, 73.08; H, 4.69; N, 9.01%. 4.25. 2-butyl-10,12-diphenyl-8-(4-methoxyphenyl)-5,5-difluoro2,4b,5a,8-tetraaza-5-bora-indeno[2,1-b]fluorene-1,9-dione (12b) The product was isolated as a green solid (92 mg, 71%). Mp > 250  С; 1H NMR (500 MHz, CDCl3): dH 7.70e7.55 (m, 4H), 7.53e7.31 (m, 9H), 7.26 (s, 1H), 6.95 (d, J ¼ 8.6 Hz, 2H), 6.88 (d, J ¼ 7.2 Hz, 1H), 6.79 (d, J ¼ 7.4 Hz, 1H), 3.90 (t, J ¼ 7.2 Hz, 2H), 3.81 (s, 3H), 1.75e1.64 (m, 2H), 1.42e1.32 (m, 2H), 0.92 (t, J ¼ 7.2 Hz, 3H); LC-MS: m/z 641 ([M þ H]þ). Anal. calcd for C38H31BF2N4O3: C, 71.26; H, 4.88; N 8.75%. Found C, 71.58; H, 4.63; N, 8.54%. 4.26. 2-butyl-10,12-diphenyl-8-(4-ethoxyphenyl)-5,5-difluoro2,4b,5a,8-tetraaza-5-bora-indeno[2,1-b]fluorene-1,9-dione (12c)

8.60e8.53 (m, J ¼ 4.4 Hz, 1H), 7.98 (d, J ¼ 7.7 Hz, 1H), 7.80e7.72 (m, 2H), 7.65e7.55 (m, 4H), 7.50e7.37 (m, 7H), 7.35 (d, J ¼ 7.3 Hz, 1H), 7.31e7.26 (m, 1H), 6.98 (d, J ¼ 7.4 Hz, 1H), 6.79 (d, J ¼ 7.4 Hz, 1H), 3.90 (t, J ¼ 7.3 Hz, 2H), 1.76e1.64 (m, 2H), 1.44e1.30 (m, 2H), 0.92 (t, J ¼ 7.3 Hz, 3H); LC-MS: m/z 612 ([M þ H]þ). Anal. calcd for C36H28BF2N5O2: C, 70.72; H, 4.62; N 11.45%. Found C, 70.96; H, 4.51; N, 11.32%. Acknowledgment This work was partially financially supported by the NATO “Science for Peace” program, project NUKR.SFPP 984189. Appendix A. Supplementary data Supplementary data related to this article can be found at http:// dx.doi.org/10.1016/j.dyepig.2014.11.016. References

The product was isolated as a green solid (91 mg, 70%). Mp > 250  С; 1H NMR (500 MHz, CDCl3): dH 7.70e7.54 (m, 4H), 7.53e7.36 (m, 8H), 7.34 (d, J ¼ 7.3 Hz, 1H), 7.22 (s, 1H), 6.93 (d, J ¼ 8.6 Hz, 2H), 6.87 (d, J ¼ 7.1 Hz, 1H), 6.79 (d, J ¼ 7.3 Hz, 1H), 4.03 (q, J ¼ 6.8 Hz, 2H), 3.90 (t, J ¼ 7.2 Hz, 2H), 1.76e1.62 (m, 2H), 1.40 (t, J ¼ 6.8 Hz, 3H), 0.92 (t, J ¼ 7.2 Hz, 3H); LC-MS: m/z 655 ([M þ H]þ). Anal. calcd for C39H33BF2N4O3: C, 71.57; H, 5.08; N 8.56%. Found C, 71.83; H, 4.88; N, 8.31%. 4.27. 2-butyl-10,12-diphenyl-8-[(3-trifuoromethyl)phenyl]-5,5-difluoro2,4b,5a,8-tetraaza-5-bora-indeno[2,1-b]fluorene-1,9-dione (12d) The product was isolated as a green solid (82 mg, 64%). Mp > 250  С; 1H NMR (500 MHz, CDCl3): dH 7.70e7.54 (m, 8H), 7.50e7.34 (m, 9H), 6.96 (d, J ¼ 7.1 Hz,1H), 6.79 (d, J ¼ 7.1 Hz,1H), 3.90 (t, J ¼ 7.2 Hz, 2H), 1.76e1.64 (m, 2H), 1.43e1.31 (m, 2H), 0.93 (t, J ¼ 7.2 Hz, 3H); LC-MS: m/z 679 ([M þ H]þ). Anal. calcd for C38H28BF5N4O2: C, 67.27; H, 4.16; N 8.26%. Found C, 67.54; H, 4.04; N, 8.04%. 4.28. 2-butyl-10,12-diphenyl-8-(2-fuorophenyl)-5,5-difluoro2,4b,5a,8-tetraaza-5-bora-indeno[2,1-b]fluorene-1,9-dione (12e) The product was isolated as a green solid (94 mg, 75.1%). Mp > 250  С; 1H NMR (500 MHz, CDCl3): dH 7.67e7.55 (m, 4H), 7.52e7.31 (m, 12H), 7.23e7.17 (m, 1H), 6.93 (d, J ¼ 7.0 Hz, 1H), 6.79 (d, J ¼ 7.0 Hz, 1H), 3.90 (t, J ¼ 7.0 Hz, 2H), 1.75e1.64 (m, 2H), 1.43e1.31 (m, 2H), 0.93 (t, J ¼ 7.0 Hz, 3H); LC-MS: m/z 629 ([M þ H]þ). Anal. calcd for C37H28BF3N4O2: C, 70.71; H, 4.49; N 8.92%. Found C, 70.93; H, 4.28; N, 8.77%. 4.29. 2-butyl-10,12-diphenyl-8-(4-nitrophenyl)-5,5-difluoro2,4b,5a,8-tetraaza-5-bora-indeno[2,1-b]fluorene-1,9-dione (12f) The product was isolated as a green solid (91 mg, 70.0%). Mp > 250  С; 1H NMR (500 MHz, CDCl3): dH 8.32 (d, J ¼ 8.7 Hz, 2H), 7.65e7.53 (m, 8H), 7.53e7.34 (m, 9H), 6.99 (d, J ¼ 7.2 Hz, 1H), 6.78 (d, J ¼ 7.2 Hz, 1H), 3.90 (t, J ¼ 7.3 Hz, 2H), 1.75e1.64 (m, 2H), 1.43e1.31 (m, 2H), 0.93 (t, J ¼ 7.3 Hz, 3H); LC-MS: m/z 656 ([M þ H]þ). Anal. calcd for C37H28BF2N5O4: C, 67.80; H, 4.31; N 10.68%. Found C, 68.03; H, 4.22; N, 10.52%. 4.30. 2-butyl-10,12-diphenyl-8-(pyridin-2-yl)-5,5-difluoro2,4b,5a,8-tetraaza-5-bora-indeno[2,1-b]fluorene-1,9-dione (12g) Time of refluxing e 24 h. The product was isolated as a green solid (85 mg, 70%). Mp > 250  С; 1H NMR (500 MHz, CDCl3): dH

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