Printer Friendly

Synthesis of 8-substituted 4, 4-difluoro-4-bora-3a,4a-diaza-s-indacene Dyes (BODIPY).

Byline: AHMET TUTAR, RAMAZAN ERENLER AND JEAN-FRANCOIS BIELLMANN

Summary: 4,4-Difluoro-4-bora-3a,4a-diaza-s-indacene (BODIPY) dyes are important in synthetic and applied chemistry. The reaction of pyrrolomethane 1 with acetyl chloride and boron trifluoride etherate in the presence of triethylamine afforded the 4,4-Difluoro-3,5,8-trimethyl-4-bora-3a,4a- diaza-s-indacene 2a. When benzoylchloride and chloroacetyl chloride were used, phenyl 2b and chloromethyl 2c derivatives formed. The treatment of pyrrolomethane 1 with 3- (phenylthio)propanal 3 in the presence of ytterbium (III) trifluoromethanesulfonate hydrate in catalitic amount yielded the 5-(2-thiophenyl ethane)-1,9-dimethyldipyrromethane 4, which was reacted with DDQ and boron trifluoride etherate in the presence of triethylamine formed 8-(2-thiophenylethan) 4,4-difluoro-3,5dimethyl-4-bora-3a,4a-diaza-3-indacene 5. The oxidation of 8-(thiomethyl) 4,4-difluoro-3,5- dimethyl-4-bora-3a,4a-diaza-s-indacene 6 with m-CPBA gave methylsulfonyl product 7.

Bromination of 4,4-difluoro-3,5,8-trimethyl-4-bora-3a,4a-diaza-s-indacene 2a yielded 1,2,6,7- tetrabromo-4,4-difluoro-3,5,8-trimethyl-4-bora-3a,4a-diaza-s-indacene 8.

4,4-Difluoro-4-bora-3a,4a-diaza-s-indacene (BODIPY) dyes have attracted much attention due to the excellent applications in many areas such as fluorescent switches [1, 2], supramolecular polymers [3-5], labeling reagents [6-8], chemosensors [9-11], near-IR absorbing/emitting dyes [12-14], nonlinear optical materials [15, 16], photodynamic therapy [17-19], chromogenic probes [20], laser dyes [21], light-harvesters and sensitizers for solar cell applications [22]. BODIPY dyes tend to be strongly UV- absorbing small molecules that emit relatively sharp fluorescence peaks with high quantum yields. Small modifications to their structures enable tuning of their fluorescence characteristics; consequently, these dyes are widely used to label proteins [23] and DNA [24].

Herein, we report the synthesis of substituted BODIPY compounds under mild reaction conditions in reasonable yield. The structures of synthesised compounds were identified by spectroscopic techniques, including 1H-, 13C-NMR IR, MS, micro analysis.

Result and Discussion

The treatment of pyrrolomethane 1 with acetyl chloride and boron trifluoride etherate in the presence of triethylamine gave 4,4-Difluoro-3,5,8- trimethyl-4-bora-3a,4a-diaza-s-indacene 2a. The 1H- spectrum of 2a displayed the signals at Delta 2.48 which belonged to methyl bonded to C-8 carbon. On the other hand, the singlet observed at Delta 2.58 which belonged to methyl groups attached to C-3 and C-5 carbons. The characteristic doublet appeared at Delta 6.24 with a coupling constant as 4.3 Hz assigned to the methine protons (H-1 and H-7) and the other methine protons (H-2 and H-6), resonated at Delta 7.06, coupled with H-1 and H-7 as the same coupling constant. In the 13C-spectrum, the observation of seven peaks is fully in agreement with the 4,4-Difluoro-3,5,8- trimethyl-4-bora-3a,4a-diaza-s-indacene 2a.

When benzoylchloride and chloroacetyl chloride were used instead of acetyl chloride, corresponding 4,4- Difluoro-8-phenyl-3,5-dimethyl-4-bora-3a,4a-diaza-s-indacene 2b and 4,4-difluoro-8-chloromethyl-3,5- dimethyl-4-bora-3a,4a-diaza-s-indacene 2c were formed, respectively. The 1H-spectrum of compound 2b resembled the spectrum of compound 2a but compound 2b consisted of phenyl instead of methyl that the compound 2a contained. In 1H-spectrum, phenyl protons resonated at Delta 7.45 as multiplet, H-1 and H-7 gave the signal at Delta 6.90 as doublet (J = 3.7), and the signal observed at Delta 6.24 as doublet (J = 3.7) could be attributed to the H-2 and H-6.

The appearance of ten lines in C spectrum was also accordance with the proposed structure, compound 2b. The

H spectrum of compound 2c showed the singlet at aliphatic region as Delta 4.56 and other signals looked like the compound 2a and 2b. The seven lines in 13C spectrum and other spectroscopic data confirmed the proposed structure. The reaction of pyrrolomethane 1 with 3- (phenylthio)propanal 3 in the presence of ytterbium (III) trifluoromethan- esulfonate hydrate in catalytic amount gave the 5-(2- thiophenyl ethane)-1,9-dimethyldipyrromethane 4, which was treated with DDQ and boron trifluoride etherate in the presence of triethylamine yielded 8-(2- thiophenylethan) 4,4-difluoro-3,5dimethyl-4-bora-3a,4a-diaza-3-indacene 5. In 1H spectrum of compound 4, the signals appeared at Delta 7.52 as broad singlet that belonged to the proton attached to nitrogen. While the phenyl protons resonated at Delta 7.30-7.12, the methyl groups gave the signal at Delta 2.19. The appearance of the other protons in expected location confirmed the structure of compound 4.

In the 1H spectrum of compound 5, The aromatic protons gave the signals at Delta 7.3-7.24. The signal of H-1 and H-7 appeared at Delta 6.86 as doublet (J = 4.2 Hz) and the resonance appeared at Delta 6.21 as doublet (J = 4.2) could be ascribed to H-2 and H-6. The aliphatic protons gave rise to AA' and BB' at Delta 3.15 and Delta 3.0 and methyls signal appeared at 2.57 as singlet. The observation of twelve lines in 13C spectrum verified the proposed structure. 8- (thiomethyl) 4,4-difluoro-3,5-dimethyl-4-bora-3a,4a- diaza-s-indacene 6 was synthesised according to the study carried out by Biellmann et al [25].

The oxidation of 8-(thiomethyl) 4,4-difluoro-3,5- dimethyl-4-bora-3a,4a-diaza-s-indacene 6 with m- CPBA gave methylsulfonyl product 7 in a yield of 10%.

The bromination reactions are prominent in synthetic chemistry [26, 27]. Due to the importance of brominated compounds as precursors in the preparation of organometallic reagents [28] and metal mediated coupling reactions [29], we brominated 4,4- difluoro-3,5,8-trimethyl-4-bora-3a,4a-diaza-s- indacene 2a in tube to yield 1,2,6,7-tetrabromo-4,4- difluoro-3,5,8-trimethyl-4-bora-3a,4a-diaza-s- indacene 8 (scheme). In 1H spectrum of compound 8, the appearance of only methyl peaks at Delta 3.09 and Delta 2.60 indicated that addition-elimination reaction took place and four bromines were bonded to the compound 2a. In addition, seven lines in 13C spectrum were in accordance with the proposed structure.

Experimental General Procedure

Commercial reagents were purchased from standard chemical suppliers and purified if needed. Flash column chromatography was carried out on Silica Gel 60 (230-400 mesh, E. Merck). TLC was performed on pre-coated glass plates of Silica Gel 60 F254 (0.25 mm, E. Merck), detection was done by spraying with a solution of Ce(NH4h(N03)6, (NH4)6M07024, and H2S04 in water or ninhydrin and acetic acid solution in n-butanol and subsequent heating on a hot plate. Melting points were determined with a Biichi B-540 apparatus and are uncorrected. IH and l3C spectra were recorded with Bruker 300 MHz instruments. Chemical shifts are in ppm from TMS as internal standard; generated from the CDCl3. IR spectra were taken with a Perkin- Elmer Paragon 1000 FT-IR spectrometer. Elemental analysis was done with a Perkin-Elmer 2400CHN instrument. Mass spectra were obtained with a FAB JMS-700 double focusing mass spectrometer (JEOL, Tokyo, Japan).

Synthesis of 4,4-Difluoro-3,5,8-trimethyl-4-bora-3a,4a-diaza-s-indacene 2a (BODIPY-2a)

To a solution of 2-Methylpyrrole 1 (1.9 g, 23 mmol) in C2H4Cl2 (10 mL) was dropwise added a solution of acetyl chloride (2.33 mL, 32 mmol) in C2H4Cl2 (10 mL) at room temperature for 30 min under nitrogen. After addition, the solution was stirred at room room temperature for 12 h under nitrogen. The solution was cooled to 0 oC ice-water bath, triethylamine (7 ml, 50 mmol) was then added dropwise at 0 oC for 10 min, and the mixture was stirred for 10 min. The ice-water bath was removed. After reaction mixture was reached to room temperature, then BF3 etherate (11 mL, 90 mmol) was added, and the mixture was stirred at room temperature for 1h. After removal of solvent, the residue was passed through a silica gel column using 10% EtOAc in hexanes to give 4 as a deep purple needles crystalline product after removal of solvent (0.57 g, 21%). mp 121-123 oC. umax IR (CH2Cl2)/cm-1 705, 752, 1151, 1270, 1497, 1581. Delta H (CDCl3, 300 MHz) 7.06 (d, J 4.3 Hz, 2H), 6.24 (d, J 4.3 Hz, 2H),2.58 (s, 6H), 2.48 (s, 3H).

Delta C (CDCl3, 75 MHz) 156.5,140.1, 134.9, 126.9, 118.7, 15.1, 14.7. MS (FAB+,NBA) m/z 234.2 (M+). Anal. Calcd. For C12H13BF2N2; C, 61.58; H, 5.60; N, 11.97. Found; C,61.22; H, 5.82; N, 11.21.

Synthesis of 4,4-Difluoro-8-phenyl-3,5-dimethyl-4- bora-3a,4a-diaza-s-indacene 2b (BODIPY-2b)

To a solution of 2-methylpyrrole 1 (1.81 g,22 mmol in C2H4Cl2 (10 mL) was added a solution of benzoylchloride (3.14 g, 22 mmol) in C2H4Cl2 (10 mL) dropwise at room temperature for 30 min under nitrogen. After addition, the solution was refluxed for 12 h under nitrogen. A black solution was formed. The solution was cooled to room temperature, then triethylamine (7 mL, 50 mmol) was added dropwise at room temperature for 10 min under nitrogen. After the addition, the dark solution was further stirred for 10 min at room temperature. Then BF3 etherate (11 ml, 90 mmol) was added, and the mixture was refluxed for 1 h under nitrogen. The solvent was removed, and the residue was passed through a silica gel column using 10% EtOAc in hexanes to give 2b as a deep purple needles crystalline product after removal of solvent (1.7 g, 53%). mp 131-132 oC.

umax IR (CH2Cl2)/cm-1 440, 705, 1011, 1153, 1269, 1499, 1560). Delta H (CDCl3, 300 MHz) 7.45 (m, 5H), 6.90 (d, J 3.7 Hz, 2H), 6.24 (d, J 3.7 Hz, 2H), 2.64 (s, 6H).

Delta C (CDCl3, 75 MHz) 157.5, 142.5, 134.5, 134.0, 130.4, 130.3, 129.9, 128.1, 119.3, 14.8. MS (FAB+, NBA) m/z 296.1 (M+). Anal. Calcd. For C17H15BF2N2; C,68.95; H, 5.11; N, 9.46. Found; C, 68.65; H, 5.13; N,9.08.

Synthesis of 4,4-Difluoro-8-chloromethyl-3,5- dimethyl-4-bora-3a,4a-diaza-s-indacene 2c (BODIPY-2c)

To a solution of 2-Methylpyrrole 1 (2.48 g,30.6 mmol) in C2H4Cl2 (10 mL) was added dropwise a solution of chloroacetyl chloride (2.50 mL, 30.6 mmol) in C2H4Cl2 (10 mL) at room temperature for 30 min under nitrogen. After addition, the solution was stirred at room temperature for 12 h under nitrogen. A black solution was formed. Triethylamine (8.5 mL, 60.2 mmoL was then added dropwise at 0oC for 10 min under nitrogen, and the mixture was stirred for 10 min. Then BF3 etherate (15.4 mL, 122.4 mmol) added, and the mixture was stirred at room temperature for 1h. After removal of solvent, the residue was passed through a silica gel column using 10% EtOAc in hexanes to give 2c as a black fine solid after removal of solvent (0.87, 21%). mp 155-157 oC.

Delta H (CDCl3, 300 MHz) 7.12 (d, J 4.2 Hz, 2H),6.28 (d, J 4.2 Hz, 2H), 4.56 (s, 2H), 2.59 (s, 6H). Delta C (CDCl3, 75 MHz) 159.2, 135.6, 134.1, 127.1, 119.9,37.4, 15.0. MS (FAB+, NBA) m/z 268.1 (M+). Anal.Calcd. For C H BClF N ; C, 53.68; H, 4.50; N,10.43. Found; C, 53.45; H, 4.53; N, 10.18.

Synthesis 5-(2-thiophenyl ethane)-1,9- dimethyldipyrromethane 4

To a 0.1 M ytterbium (III) trifluoromethanesulfonate hydrate (0.62 g) in solution of ethanol/water (7 mL/3 mL) was added 2- methylpyrrole (1.62 g, 20 mmol) and 3- (phenylthio)propanal (0.83 g, 5 mmol). The reaction mixture was stirred 3 h at room temperature. After stirring, to the reaction mixture was added saturated NaHCO3 (50 mL), extracted three times with ether (totally 75 mL). The combined organic layer was washed with brine. The extract was then dried over MgSO4 and purified by flash column chromatograpy (silica gel 60, 70-230 mesh). The pyrromethane 4 was otained as yellow liquid (0.71g, 46%). Delta H (CDCl3, 300 MHz) 7.52 (brd s, 2H, NH) 7.30-7.12 (m, 5H), 5.93 (d, J 4.8 Hz, 2H), 5.80 (d, J 4.8 Hz,2H), 4.11 (t, J 7.8 Hz 1H), 2.93 (t, J 7.5 Hz 2H) 2.22 (dt, 2H) 2.19 (s, 6H). Anal. Calcd. For C19H22N2S; C,73.51; H, 7.14; N, 9.02. Found; C, 73.31; H, 7.02; N,9.23.

Synthesis of 8-(2-thiophenylethan) 4,4-difluoro-3,5dimethyl-4-bora-3a,4a-diaza-3-indacene 5 (BODIPY-5)

A 0,65 g sample (2.1 mmol) of 1,9- dimethyl-5-(thiophenylethane)dipyrromethane was dissolved in 10 mL toluene at room temperature in a 25 mL one-neck round flask. DDQ (470 mg, 2.1 mmol) was added at once and the reaction mixture was stirred at room temperature. After 5 min, triethylamine (2 mL, 14 mmol) was added to the black reaction mixture followed immediately by BF3- etherate (4 mL, 31.8 mmol) under nitrogen at room temperature. After 1 h, the reaction mixture was rotary evaporated to a black viscous material. Column chromatography (silica gel, ethyl acetate/hexanes, 1/9) gave the desired product, which eluted as the first component. Removal of the solvent gave 210 mg (28%) of the title compound as a deep red oily liquid. Delta H (CDCl3, 300 MHz) Delta 7.36-7.24 (m,5H), 6.86 (d, J = 4.2 Hz, 2H), 6.21 (d, J = 4.2 Hz,2H), 3.15 (AA' part of AA'BB', 2H), 3.00 (BB' part of AA'BB', 2H) 2.57 (s, 6H). Delta C (CDCl3, 75 MHz) 157.2, 141.4, 134.8, 134.3, 130.4, 129.1, 126.9, 126.6, 119.0, 36.8, 30.3, 14.7.

Anal. Calcd. For C19H19BF2N2S; C, 64.06; H, 5.38; N, 7.86. Found; C,63.91; H, 5.25; N, 7.91.

Oxidation 8-(thiomethyl) 4,4-difluoro-3,5-dimethyl-4- bora-3a,4a-diaza-s-indacene 6 (BODIPY-6) to Sulfone 7

A mixture of BODIPY-6 (87 mg, 0.3 mmol) and m-CPBA (0.172 g, 0.9 mmol) in dry CH2Cl2 (5 mL) was heated to reflux for 3 h under nitrogen atmosphere. After cooling, the reaction mixture was washed with a mixture of saturated NaHCO3 and 10% NaHSO3 solution and extracted with CH2Cl2.

The solution was dried and chromatographed and SiO2 column. Elution with n-hexane and ethyl acetate (4:1) provided 8-(sulfone) 4,4-difluoro-3,5-dimethyl-4-bora-3a,4a-diaza-s-indacene 7 in 10% yield (8.9 mg). Delta H (CDCl3, 300 MHz) 7.76 (A part of AB system, 2H, J = 4.4 Hz), 6.37 (B part of AB system,2H, J = 4.4 Hz), 2.72 (s, 3H), 2.57 (s, 6H). MS (EI+) m/z 298.1 [M]+.

Bromination of BODIPY-2a: Synthesising of tetrabromo-4,4-difluoro-3,5,8-trimethyl-4-bora-3a,4a-diaza-s-indacene 8

A solution of a trace of 2a in CDCl3 in tube was added 1-2 drops bromine at room temperature. The 1H-and 13C-spectra were recorded. Spectral data indicated the formation of 1,2,6,7-tetrabromo-4,4- difluoro-3,5,8-trimethyl-4-bora-3a,4a-diaza-s- indacene 8 as the sole product. Mp188-190 oC. Delta H (CDCl3, 300 MHz) 3.09 (s, 3H), 2.60 (s, 6H). Delta C (CDCl3, 75 MHz) 153.5, 129.0, 120.4, 114.2, 105.5,17.2, 14.2. MS (FAB+, NBA) m/z 545.8 (M+). Anal.

Calcd. For C12H9BBr4F2N2; C, 26.22; H, 1.65; N,5.11. Found; C, 26.11; H, 1.37; N, 5.22.

Conclusion

Due to the many application area of BODIPY, synthesising of 8-substituted 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene dyes (BODIPY) under mild reaction conditions in reasonable yield could be the significant for applied chemistry. In addition, Brominated BODIPY could be the valuable precursor for functionalisation of the BODIPY core by coupling reactions.

References

1. T. K. Khan, R. R. S. Pissurlenkar, M. S. Shaikh and M. Ravikanth, Journal of Organometallic Chemistry, 697, 65 (2012).

2. B. Brizet, A. Eggenspiller, C. P. Gros, J. M.Barbe, C. Goze, F. Denat and P. D. Harvey,Journal of Organic Chemistry, 77, 364 (2012).

3. S. Diring, F. Puntoriero, F. Nastasi, S. Campagna and R. Ziessel, Journal of the American Chemical Society, 131, 6108 (2009).

4. T. K. Khan, M. S. Shaikh and M. Ravikanth,Dyes and Pigments, 94, 66 (2012).

5. T. A. Golovkova, D. V. Kozlov and D. C.Neckers, Journal of Organic Chemistry, 70,5545 (2005).

6. R. P. Haugland, The Handbook: A Guide to Fluorescent Probes and Labeling Technologies,10th ed.; Invitrogen Corp.: Eugene (OR, USA),2005.

7. L. Pu, Chemistry Review, 104, 1687 (2004).

8. R. Martinez-Manez and F. Sancenon, Chemistry Review, 103, 4419 (2003).

9. A. Coskun and E. U. Akkaya, Journal of the American Chemical Society, 127, 10464 (2005).

10. K. Rurack, M. Kollmannsberger, U. Resch- Genger and J. Daub, Journal of the American Chemical Society, 122, 968 (2000).

11. Z. Ekmekci, M. D. Yilmaz and E. U. Akkaya, Organic Letters, 10, 461 (2008).

12. S. Ito, T. Murashima, N. Ono and H. Uno,Chemical Communications, 1661 (1998).

13. W. L. Zhao and E. M. Carreira, Angewandte Chemie, International Edition, 44, 1677 (2005).

14. C. Goze, G. Ulrich, L. J. Mallon, B. D. Allen, A.Harriman and R. Ziessel, Journal of the American Chemical Society, 128, 10231 (2006).

15. S. Mula, G. Ulrich and R. Ziessel, Tetrahedron Letters, 50, 6383 (2009).

16. J. H. Olivier, J. Barbera, E. Bahaidarah, A.Harriman and R. Ziessel, Journal of the American Chemical Society, 134, 6100 (2012).

17. S. Atilgan, Z. Ekmekci, A. L. Dogan, D. Guc and E. U. Akkaya, Chemical Communication,4398 (2006).

18. S. H. Lim, C. Thivierge, P. Nowak-Sliwinska, J.Han, H. van den Bergh, G. Wagnieres, K. Burgess and H. B. Lee, Journal of Medicinal Chemistry, 53, 2865 (2010).

19. F. Bergstrom, L. Mikhalyov and L. B.-A.Johansson, Journal of the American Chemical Society, 124, 196 (2002).

20. A. Loudet, K. Burgess, Chemistry Review, 107,4891 (2007).

21. R. Ziessel, G. Ulrich and A. Harriman, New Journal of Chemistry, 31, 496 (2007).

22. A. Loudet and K. Burgess, Chemistry Review,107, 4891 (2007).

23. J. Karolin, L. B.-A. Johansson, L. Strandberg, T.Ny, Journal of the American Chemical Society,116, 7801 (1994).

24. S. A. Farber, M. Pack, S. Y. Ho, L. D. Johnson and D. S. Wagner, Science, 292, 1385 (2001).

25. T. V. Goud, A. Tutar and J. F. Biellmann,Tetrahedron, 62, 5084 (2006).

26. O. Cakmak, R. Erenler, A. Tutar and N. Celik,Journal of Organic Chemistry, 71, 1795 (2006).

27. A. Tutar and M. Balci, Tetrahedron, 58, 8979 (2002).

28. H. L. Anderson, C. J. Walter, A. Vidal-Ferran,R. A. Hay, P. A. Lowden and J. K. M. Sanders, Journal of the Chemical Society, Perkin Transactions 1, 18, 2275 (1995).

29. I. P. Beletskaya and A. V. Cheprakov, Chemistry Review, 100, 3009 (2000).

Institute of Chemistry, Academia Sinica, Taipei 115, Taiwan.

Sakarya University, Faculty of Art and Science, Department of Chemistry, TR-54187 Sakarya, Turkey.

Gaziosmanpasa University, Faculty of Art and Science, Department of Chemistry, TR-60240 Tokat, Turkey.

National Central University Jhongli Taiwan.atutar@sakarya.edu.tr, ramazan.erenler@gop.edu.tr
COPYRIGHT 2013 Asianet-Pakistan
No portion of this article can be reproduced without the express written permission from the copyright holder.
Copyright 2013 Gale, Cengage Learning. All rights reserved.

Article Details
Printer friendly Cite/link Email Feedback
Publication:Journal of the Chemical Society of Pakistan
Article Type:Report
Geographic Code:9PAKI
Date:Aug 31, 2013
Words:3136
Previous Article:Structural Elucidation of in Vitro and in Vivo Metabolites of Emodin in Rats by LC -ESI-MS/MS.
Next Article:Study on the Way of Urea Removal by BAF.
Topics:

Terms of use | Privacy policy | Copyright © 2019 Farlex, Inc. | Feedback | For webmasters