Synthesis of 3,5-diaryl-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (BODIPY) dyes

Article abstract of DOI:10.1055/s-1998-1924

2-Aryl pyrroles 2 were formed via Suzuki coupling of arylboronic acids to N-BOC protected 2-bromopyrrole. These pyrroles were used to produce 3,5-diaryl BODIPY dyes 1 having red-shifted fluorescence maxima relative to comparable alkyl-substituted systems. Absorption and fluorescence spectra of the compounds 1 are discussed.

Full text of DOI:10.1055/s-1998-1924

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®
Synthesis of 3,5-Diaryl-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (BODIPY ) Dyes
Lars H. Thoresen, Heejin Kim, Mike B. Welch, Armin Burghart, Kevin Burgess*
Department of Chemistry, Texas A & M University, PO Box 300012, College Station, TX 77842-3012
fax 409 845 4345; email burgess@chemvx.tamu.edu
Received 4 August 1998
Abstract: 2-Aryl pyrroles 2 were formed via Suzuki coupling of
arylboronic acids to N-BOC protected 2-bromopyrrole. These pyrroles
were used to produce 3,5-diaryl BODIPY® dyes 1 having red-shifted
fluorescence maxima relative to comparable alkyl-substituted systems.
Absorption and fluorescence spectra of the compounds 1 are discussed.
aryl boronic acids with the bromopyrrole 4. To the best of our
knowledge, this approach has not been reported previously, although
Suzuki couplings of N-tert-butoxycarbonyl 2,5-dibromopyrrole have
been used as a route to polymeric products.11
4,4-Difluoro-4-bora-3a,4a-diaza-s-indacenes1 are highly fluorescent
materials2 that have a range of applications in such areas as biological
labeling and syntheses of molecular devices.3 Several of these dyes are
marketed as “BODIPY® dyes”, e.g. D-2190 (Molecular Probes Inc.,
Eugene, Oregon, USA). However, they are sold in small quantities for
biological experiments, but amounts typically required for synthetic
applications would be prohibitively expensive.
We required a set of BODIPY dyes that have functionality-allowing
connections to other molecular fragments, and distinct fluorescence
emission maxima. Consequently,
a divergent route to the title
compounds 1 was sought. In this structure, the aryl iodide at the
dipyrromethene meso-position facilitates elaboration via organometallic
coupling reactions,4 and variation of the aryl functionality Ar allows
systematic variation of the fluorescence λmax
.
It was found that N-tert-butoxycarbonyl-2-bromopyrrole12,13 reacted
with arylboronic acids to give the protected 2-arylpyrroles 5a – d in
excellent yield. The scope of this approach is not much less than the
route involving
3 because many aryl boronic acids are now
commercially available (Frontier Scientific Inc. of Logan, Utah, USA is
a good source). Removal of the N-BOC protecting group under basic
conditions14 gave the desired 2-aryl pyrroles 2a – d. These products
decompose on standing, rapidly under acidic conditions, and are
therefore best formed immediately before use in the following step.
None of the existing procedures for making 2-arylpyrroles seemed ideal
for the divergent synthesis required in this work. The most widely used
methods involve moderate yields and long purification procedures,5 or
the necessity of preparing specific starting materials, such as 4-aryl-1-
azidobutadienes,6 or a N-tosylarylimine,7 for each product to be
prepared. Suzuki couplings8,9 of the boronic acid 3, or similarly N-
protected derivatives, were attractive insofar as this one intermediate
could be reacted with several readily available aryl iodides. However,
preliminary experiments indicated that the known instability of these
boron-substituted pyrroles10 causes problems that would not be easily
overcome. Consequently, our attention shifted to Suzuki couplings of
Formation of the BODIPY products 1 via a one-pot, two-step process
starting from 2 is possible, but better yields are usually obtained if the
intermediate dipyrrolemethenes 6 are purified before addition of the
boron source. Thus, condensation of 4-iodobenzoyl chloride with the 2-
aryl pyrroles 2 gives the highly colored dipyrrolemethenes 6; these are
best isolated via chromatography on basic alumina. Finally, addition of
boron trifluoride etherate gives the BODIPY’s 1a - d.15

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The 3,5-diaryl BODIPY dyes 1 are intensely colored both in solution
(e. g. in chloroform: 1a brick red, 1b red, 1c violet and 1d fuchsia) and
in the solid state (dark violet crystals). Figure 1a shows the absorption
spectra for the four products in chloroform and Table 1 the respective
data. Compared to the alkyl substituted BODIPY system D-219016
displaying λmax (absorption) = 495 nm and ε = 87,000 M-1 cm-1 (i) the
wavelength for the absorption for 1a – 1d is red-shifted and (ii) the
extinction coefficients are decreased. Fluorescence spectra for the four
compounds are given in Figure 1b. Interestingly, these 3,5-diaryl
BODIPY dyes exhibit larger Stokes shifts than the alkyl substituted
systems (8 nm for D-2190), especially large is that of the naphthyl
system 1b (> 50 nm). The fluorescence intensities are markedly lower
than those of alkyl substituted BODIPYs.17 This may be due to non-
radiative decay of twisted biaryl conformations in the excited state.18
In summary, Suzuki coupling of arylboronic acids to N-BOC protected
2-bromopyrrole provides an efficient route to 2-arylpyrroles 2. These
were used as starting materials to prepare the novel 3,5-diaryl BODIPY
dyes 1a – d. The absorption wavelength of compounds 1a – d is red-
shifted compared with alkyl substituted BODIPY systems.
References and Notes
Acknowledgements. Financial support was provided via NIH grant
HGO1459 and The Robert A. Welch Foundation, and K. B. thanks the
NIH for a Research Career Development Award and the Alfred P. Sloan
(1) Treibs, A.; Kreuzer, F.-H. Liebigs Ann. Chem. 1968, 718, 208.
(2) Karolin, J.; Johansson, L. B.-A.; Strandberg, L.; Ny, T. J. Am.
Chem. Soc. 1994, 116, 7801.
Foundation for
a
fellowship. A. B. thanks the Deutsche
(3) Wagner, R. W.; Lindsey, J. S. Pure & Appl. Chem. 1996, 68,
Forschungsgemeinschaft for a fellowship.
1373.
(4) Wagner, R. W.; Lindsey, J. S. J. Am. Chem. Soc. 1994, 116, 9759.
(5) Trofimov, B. A. Adv. Heterocycl. Chem 1990, 51, 177.
(6) Boukou-Poba, J. P.; Farnier, M.; Guilard, R. Tetrahedron Lett.
1979, 19, 1717.
(7) Katrizky, A. R.; Li, J.; Gordeev, M. F. Synthesis 1994, 93.
(8) Miyaura, N.; Ishiyama, T.; Sasaki, H.; Ishikawa, M.; Satoh, M.;
Suzuki, A. J. Am. Chem. Soc. 1989, 111, 314.
(9) Sato, M.; Miyaura, N.; Suzuki, A. Chem. Lett. 1989, 1405.
(10) Grieb, J. G.; Ketcha, D. M. Synth. Comm. 1995, 25, 2145.
(11) Martina, S.; Schluter, A. D. Macromolecules 1992, 25, 3607.
(12) Chen, W.; Cava, M. P. Tetrahedron Lett. 1987, 28, 6025.
(13) Chen, W.; Stephenson, E. K.; Cava, M. P.; Jackson, Y. A. Org.
Syn. 1991, 70, 151.

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(14) Hasan, I.; Marinelli, E. R.; Lin, L. C. C.; Fowler, F. W.; Levy, A.
(4 mL) were heated to reflux for 6 h, during which time the
solution gradually acquired a purple hue. The reaction mixture
was diluted with CH2Cl2 (50 mL), washed with 5% NaHCO3 (2 x
25 mL), dried (Na2SO4), filtered, and concentrated. The crude
product was purified via chromatography on basic alumina using
10% CH2Cl2/hexanes as eluant giving 6c as a dark purple solid
(140 mg, 87% yield). Rf 0.49 (20 % EtOAc/hexanes); 1H NMR
(CDCl3, 300 MHz) 3.39 (s, 6H), 6.67 (d, J = 4.2 Hz, 2H), 6.80 (d,
J = 4.2 Hz, 2H), 7.06 (d, J = 9.0 Hz, 4H), 7.32 (d, J = 8.4 Hz, 2H),
7.84 (d, J = 8.4 Hz, 2H), 7.89 (d, J = 9.0 Hz, 4H); 13C NMR
(CDCl3, 75 MHz) 51.0, 110.0, 110.7, 121.5, 123.1, 124.8, 128.1,
132.4, 136.8, 149.4, 155.9. 1c: Compound above (590 mg, 1.1
mmol), NEt3 ( 0.46 g, 3.3 mmol), and PhMe ( 30 mL) were stirred
at 25 °C for 10 min then boron trifluoride etherate (0.7 mL, 5.5
mmol) was added and heated to 80 °C for 20 min. Fluorescence
first appeared 2 min after addition of BF3 · OEt2 at 25 °C. The
crude reaction mixture was filtered through a plug of silica on
celite, then concentrated. Purification via chromatography on
basic alumina using 10% CH2Cl2/hexanes as eluant gave 1c as a
dark purple solid (640 mg, 99 % yield). m.p. 190.0 - 192.0 °C
(dec.); Rf 0.30 (20% EtOAc/hexanes); 1H NMR (CDCl3, 300
MHz) 3.83 (s, 3 H), 6.60 (d, J = 4.5 Hz, 2 H), 6.78 (d, J = 4.2 Hz,
2 H), 6.94 (d, J = 9.0 Hz, 4 H), 7.27 (d, J = 8.1 Hz), 7.84 (d, J = 7.5
Hz, 2 H), 7.87 (d, J = 9.0 Hz, 4 H); 13C NMR (CDCl3, 75 MHz)
55.2, 96.3, 113.8, 120.7, 125.0, 130.0, 131.1, 131.2, 132.1, 134.0,
135.9, 137.4, 158.6, 160.8; IR (cm-1) 3152, 2835, 1565, 1471;
HRMS (FAB, M·+) calc'd for C29H22N2O2BF2INa 629.0690,
found 629.0704.
B. J. Org. Chem. 1981, 46, 157.
(15) 5c: A Schlenk tube was charged with N-tert-butoxycarbonyl-2-
bromopyrrole (4) (1.20 g, 4.87 mmol), 4-methoxyphenylboronic
acid
(0.74
g,
4.87
mmol),
and
tetrakis(triphenylphosphine)palladium (115 mg, 0.097 mmol).
The vessel was evacuated then refilled with nitrogen three times.
Freshly distilled toluene (25 mL) and degassed methanol (3 mL)
were added via syringe. A degassed 2.0 M aq. solution of sodium
carbonate (4.87 mL, 9.74 mmol) was added in one portion. The
mixture was stirred under a nitrogen atmosphere at 80 °C (oil
bath) for 14 h. The layers were separated and the organic layer
was dried (Na2SO4) then evaporated. The resulting oil was
purified by flash chromatography eluting with 5% ethyl acetate/
hexanes to yield 1.20 g of the desired compound 5c (90% yield) as
a clear oil. Rf 0.40 (10% EtOAc/hexanes); 1H NMR (CDCl3, 300
MHz) 1.42 (s, 9 H), 3.84 (s, 3 H), 6.17 (dd, J = 3.3 Hz, 2.1 Hz, 1
H), 6.24 (t, J = 3.3 Hz, 1 H), 6.92 (d, J = 8.7 Hz, 2 H), 7.31 (2, J =
8.7 Hz, 2 H), 7.37 (dd, J = 3.3 Hz, 1.8 Hz, 1 H); 13C NMR
(CDCl3, 75 MHz) 27.5, 55.0, 83.2, 112.9, 113.3, 122.0, 130.2,
134.7, 149.2, 158.8; IR(film) (cm-1) 2980, 2933, 2836, 1735,
1314, 907, 742; HRMS (FAB, M·+) calc'd. for C16H19NO3
273.1365, found 273.1374. 2c: A suspension of sodium methoxide
(625 mg, 10.99 mmol) in MeOH (3.0 mL) was added to a stirred
solution of N-tert-butyloxycarbonyl-2-(4-methoxyphenyl)pyrrole
(1.0 g, 3.6 mmol) in THF (15 mL) and stirred at 25 °C for 3 h. The
reaction was diluted with Et2O (30 mL) and extracted with H2O (2
x 20 mL), brine (2 x 20 mL), dried (Na2SO4), filtered, and
concentrated. The crude reaction mixture was purified by flash
chromatography using hexanes to 5% EtOAc/hexanes eluant
giving 2c as white plates (550 mg, 86% yield; the sample had
analytical data in accord with the literature values Laatsch, H.;
Pudleiner, H. Liebigs Ann. Chem. 1989, 863). Rf 0.17 (10%
EtOAc/hexanes). 6c: 2-(4-Methoxyphenyl)pyrrole (100 mg, 0.58
mmol), 4-iodobenzoylchloride (354 g, 1.39 mmol), and (CH2Cl)2
(16) Haugland, R. P. Handbook of Fluorescent Probes and Research
Chemicals; 6th ed.; Molecular Probes Inc.: Eugene, OR, USA,
1996.
(17) Burgess, K.; Thoresen, L. H. unpublished results 1998.
(18) Rettig, W. Angew. Chem., Int. Ed. Engl. 1986, 25, 971.