A versatile, modular synthesis of monofunctionalized BODIPY dyes

Article abstract of DOI:10.1039/b906164a

A careful choice of the pyrrole building blocks allows the synthesis of a wide range of monohalogenated BODIPY dyes with excellent reactivity in palladium catalyzed coupling reactions. The Royal Society of Chemistry 2009.

Full text of DOI:10.1039/b906164a

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A versatile, modular synthesis of monofunctionalized BODIPY dyesw
Volker Leen, Els Braeken, Kristof Luckermans, Carine Jackers, Mark Van der Auweraer,
¨
Noel Boens and Wim Dehaen*
Received (in Cambridge, UK) 27th March 2009, Accepted 12th June 2009
First published as an Advance Article on the web 30th June 2009
DOI: 10.1039/b906164a
A careful choice of the pyrrole building blocks allows the
synthesis of a wide range of monohalogenated BODIPY
dyes with excellent reactivity in palladium catalyzed coupling
reactions.
that the synthesis of the desired products could be reduced to
the preparation of 2-acyl-5-halopyrroles 5.
Contrary to the well-known isomeric 2-acyl-4-halopyrroles
6,10 synthetic routes towards the compounds 5 are few.
Although direct halogenation of acylpyrroles11 may lead to
derivatives 5, this method has limitations. Due to the
electron withdrawing nature of the acyl substituent, direct
halogenation always produces a mixture of isomers. The
amount of the desired isomer 5 varies with the reaction
conditions, but it is never the sole product. Furthermore, it
is often hard to separate the isomers chromatographically.
After a review of the reported syntheses11 and a laborious
optimization study, we concluded that a general and selective
method for the syntheses of derivatives 5 would not be easy to
establish based on halogenation of 2-acylpyrroles.
In recent years, there has been increasing interest in the use of
fluorescent dyes, largely due to their potential applications in
molecular recognition, as labels and probes in biotechnology,
analytical chemistry, medical diagnostics, and materials
science.1 One of the most intensively studied and used
fluorescent systems is 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene,
better known as BODIPY.2 Derivatives of this compound
display many highly desirable properties, such as large molar
absorption coefficients, good photostability and relatively
high fluorescence quantum yields. Among the many appli-
cations are sensors for ions,3 pH4 and various optoelectronic
devices.5
Another option would be to halogenate pyrrole first,
followed by acylation. The strong a-selectivity of pyrrole then
ensures the correct regiochemistry.12 However, 2-halogenated
pyrrole 4 is notoriously unstable and decomposes violently
upon isolation. This seriously reduces the scope of the
literature procedure. It is only after several attempts that a
one-pot procedure could be developed (Scheme 2). Careful
temperature control proved crucial to ensure selective and
complete halogenation prior to in situ acylation. Fortunately,
both the Vilsmeier–Haack reaction and trifluoroacetylation
proceed smoothly in THF, furnishing the targeted
5-halogenated acylpyrroles 5 on a large scale (up to 50 mmol)
and with fair-to-good yields (33–64%).
Recent work in our group is focused on the synthesis
(Scheme 1) and reactivity of 3,5-dichloro-BODIPY 3.6 These
particular compounds are readily substituted by several
nucleophiles, allowing both mono and disubstitution by
changing the reaction conditions. Further exploration of these
reactive dyes showed that they can be used in palladium
catalyzed cross-coupling reactions, such as Suzuki, Stille,
Heck and Sonogashira reactions.7 Combination of these
reactions provides access to several highly interesting products
from a single platform.8
Drawbacks of the dichlorinated system are the need for
disubstitution to avoid a reactive position remaining vacant
and problems occurring during some palladium catalyzed
coupling reactions. Notably in the Sonogashira reaction, the
selectivity for monosubstitution is low and the resulting
products are hard to isolate in pure form. Also, Suzuki
reactions only proceed at an acceptable rate under microwave
irradiation. We are convinced that part of these problems can
be solved by the synthesis of monohalogenated BODIPY dyes.
However, expanding the previously reported methods6
to monohalogenation of the dipyrromethane precursors 1
resulted only in complex reaction mixtures.
Once a selective synthesis of monohalogenated pyrroles 5
was established, they were converted to the BODIPY dyes
(Table 1). This was accomplished by adding one equivalent of
phosphorus oxychloride to a mixture of acylpyrrole 5 and
pyrrole 7. The intermediate dipyrromethene was not isolated
but was complexed in situ by adding excess triethylamine and
boron trifluoride etherate to yield BODIPY dyes 8. The
BODIPY derivatives were then purified by column chromato-
graphy and were obtained in reasonable total yields. Since the
4-halogenated pyrroles 6 were available from our optimization
study, they were also subjected to this condensation. Similar
2-halogenated BODIPY dyes have been prepared before, both
Since the acid catalyzed condensation of an acylpyrrole and
a second pyrrole is a well-known method for preparing
dipyrromethenes,9 the precursors of BODIPY, we reasoned
Department of Chemistry, Katholieke Universiteit Leuven,
Celestijnenlaan 200f–bus 02404, 3001 Leuven, Belgium.
E-mail: wim.dehaen@chem.kuleuven.be; Fax: +32 16 327990;
Tel: +32 16 327439
w Electronic supplementary information (ESI) available: Representative
synthetic data and spectral characterization. See DOI: 10.1039/b906164a
Scheme 1 Synthesis of 3,5-dichloro-BODIPY from dipyrromethane
precursors.
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Table 2 Reactivity of the obtained dyes in palladium catalyzed
coupling reactions
Scheme 2 Selective synthesis of halogenated acylpyrroles.
Table 1 Condensation of halogenated pyrroles to the corresponding
BODIPY dyes
Reaction Type
Sonogashira
X (position)
R
Yield (%)
Product
Cl (3)
Br (3)
Br (2)
I (2)
Cl (3)
I (2)
Cl (3)
Br (3)
I (2)
Ph
Ph
Ph
Ph
TMS
TMS
—
—
—
46
74
64
75
59
81
93
86
79
9a
9a
9b
9b
9c
9d
10a
10a
10b
Suzuki
yields and is well established for pyrrole,14 allowing for a large
number of substituents to be introduced.
After successful synthesis of the desired monohalogenated
dyes, they were subjected to palladium catalyzed reactions
(Table 2). Indeed, both the 2- and 3-halogenated products
react with acetylenes under standard Sonogashira conditions.
Reaction of the 2-chlorinated dyes resulted in very low yields,
even under forcing conditions. The 2-brominated compounds
reacted in high yield, while the 2-iodinated molecules reacted
even at room temperature. All 3-halogenated dyes were
reactive in the Sonogashira reaction. The substituents on the
second pyrrole moiety decrease the reactivity of the halogen,
and the reaction is slower than observed for the dichloro-
BODIPY 3, but this could be circumvented by adapting
our reported procedure.7 Favorably, the Suzuki reaction
proceeded under conventional heating, relieving the need for
microwave irradiation. As expected, the reactivity increased
when changing from chlorine to bromine and iodine, with
excellent yields obtained in all cases.
X(position)
R
H
R1
R2
R3
Yielda (%) Product
Cl (3)
Cl (3)
Cl (3)
Cl (3)
Cl (3)
Br (3)
Cl (2)
Br (2)
Br (2)
I (2)
CH3
H
H
H
CH3
CH3
Ph
90
72b
36
31
43
62
36
57
59
25
40
8a
8b
8c
8d
8e
8f
8g
8h
8i
CH3 CH3
CH3
CH3
Ph
CH3 CH3
CH3 CH3
CH3 CH3
CH3
CH3
CH3 CH3
H
H
CH3
Cyclohexyl
H
H
H
H
CH3
CH3
CH3
CH3
H
H
DHBIc
H
H
Ph
CH3
8j
8k
I (2)
a
b
Non-optimized yields for a single 0.5 mmol experiment. Non-
c
optimized yield for a single 5 mmol experiment. DHBI stands for
4,5-dihydro-1H-benzo[g]indole.
by a condensation approach and halogenation of BODIPY,13
but they always had multiple other substituents to ensure
selective halogenation. In our modular approach one can
choose between several widely available pyrroles as the second
moiety of the target BODIPY and this selection will signifi-
cantly affect the properties of the resulting dye. For example,
replacing the commercially available 3,5-dimethylpyrrole with
the conformationally restricted 4,5-dihydro-1H-benzo[g]indole
results in dye 8i with red-shifted spectra. Moreover, selection
of the halogen allows tuning of the reactivity of the resulting
BODIPY.
As the Suzuki and Sonogashira coupling reactions lead to
excellent probes, and are of great synthetic importance for the
application of halogenated BODIPY dyes, these compounds
could be a solution to the aforementioned problematic
reactivity of the dichlorinated BODIPY dyes 3.
Although all the resulting dyes are strongly fluorescent, one
can see striking differences between the 2- and 3-substituted
dyes (Table 3). The 3-alkynated dyes 9a and 9c show very high
fluorescence quantum yields Ff, which decrease slightly upon
increasing solvent polarity. Conversely, the corresponding
2-alkynated dyes 9b and 9d have lower Ff which decrease
significantly with increasing solvent polarity, especially in
acetonitrile. Moreover, the absorption maxima of the 3-alkynyl
substituted dyes 9a and 9c are red shifted compared with those
Finally, the meso-substituent of the BODIPY results from
standard pyrrole acylation chemistry, most notably the
Vilsmeier–Haack reaction. This reaction generally gives high
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Table 3 Absorption and emission profiles of 9a (red) and 9b (orange)
in toluene spectroscopic data (absorption maxima labs, emission
maxima lem, Stokes shift Dnꢀ) and fluorescence quantum yield (Ff) of
selected substituted compounds in different solvents
pyrroles can have a profound effect on the properties of the
resulting products.
In conclusion, through an easy and selective synthesis of
halogenated acylpyrroles, we have been able to prepare several
new reactive BODIPY dyes in good total yields. These dyes
show a range of tunable properties making the possibilities of
this approach numerous. We are currently performing a
detailed study of the reactivity of these halogenated dyes as
well as a full spectroscopic/photophysical characterization.
The results hereof will be reported in due course.
The authors want to thank the I.W.T. (doctoral fellowship
to V.L.), the F.W.O.-Vlaanderen, the Ministerie voor
Wetenschapsbeleid and the University of Leuven for financial
support.
Notes and references
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´ ´ ´
BODIPY
Solvent
l
abs/nm
l
em/nm
Dnꢀ/cmÀ1
Ff
4419; (b) B. Valeur, Molecular Fluorescence. Principles
and Applications, Wiley-VCH, Weinheim, Germany, 2002;
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Oregon, USA, 10th edn, 2005.
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4 W. Qin, M. Baruah, W. De Borggraeve and N. Boens,
J. Photochem. Photobiol., A, 2006, 183, 190.
9a
Toluene
THF
MeOH
MeCN
Toluene
THF
MeOH
MeCN
Toluene
THF
MeOH
MeCN
Toluene
THF
MeOH
MeCN
Toluene
THF
MeOH
MeCN
Toluene
THF
542
535
530
525
521
513
507
503
524
518
515
512
516
507
502
498
527
522
517
513
567
560
556
556
556
551
548
545
561
569
566
566
535
530
526
525
536
540
533
533
553
549
545
543
583
577
574
574
465
543
620
699
1369
1918
2056
2213
392
437
406
484
723
1205
1159
1319
892
942
994
0.93
0.93
0.85
0.77
0.61
0.50
0.37
0.25
0.92
0.93
0.93
0.80
0.85
0.78
0.74
0.55
0.83
0.86
0.79
0.85
0.87
0.74
0.79
0.58
9b
9c
9d
10a
8i
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1077
484
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564
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of the respective 2-alkynyl isomers 9b and 9d. In contrast, in
solvents of intermediate and high polarity, the emission
maxima of 9a and 9c are blue-shifted in comparison with
those of 9b and 9d, respectively, resulting in small Stokes shifts
for the 3-alkynyl isomers 9a and 9c.
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Compound 10a has relatively high Ff values, which are
much higher than those reported for 3,5-diphenyl and
3-chloro-5-phenyl substituted BODIPY dyes.11 The methyl
group at the 5-position apparently has
fluorescence enhancement effect.
a significant
12 (a) G. Cordell, J. Org. Chem., 1975, 40, 3161; (b) H. Gilow and
D. Burton, J. Org. Chem., 1981, 46, 2221.
As an example of the versatility of our approach, one can
see that the conformationally restricted dye 8i has strongly
red-shifted absorbance and fluorescence emission maxima,
even without the presence of an alkynyl substituent. It is
also noticeable that Ff of 8i remains high, even though
bromination at the 2-position has been used in the literature
to induce triplet state formation for photodynamic therapy.15
This example thus shows that a correct choice of the starting
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Chem.–Eur. J., 2003, 9, 4430; (d) D. Zhang, Y. Wen, Y. Xiao,
G. Yu, Y. Liu and X. Qian, Chem. Commun., 2008, 4777.
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15 A. Gorman, J. Killoran, C. O’Shea, T. Kenna, W. Gallagher and
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Chem. Commun., 2009, 4515–4517 | 4517