2- and 3-monohalogenated BODIPY dyes and their functionalized analogues: Synthesis and spectroscopy

Article abstract of DOI:10.1002/ejoc.201100324

Starting from appropriately halogenated acylpyrroles, a wide range of reactive 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (BODIPY) derivatives can be obtained. The fluorescent dyes display excellent reactivity in nucleophilic aromatic substitution, transi

Full text of DOI:10.1002/ejoc.201100324

FULL PAPER
DOI: 10.1002/ejoc.201100324
2- and 3-Monohalogenated BODIPY Dyes and Their Functionalized
Analogues: Synthesis and Spectroscopy
Volker Leen,[a] Tom Leemans,[a] Noël Boens,[a] and Wim Dehaen*[a]
Keywords: Dyes / Fluorescent probes / Click chemistry / Cross-coupling
Starting from appropriately halogenated acylpyrroles, a wide
range of reactive 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene
(BODIPY) derivatives can be obtained. The fluorescent dyes
display excellent reactivity in nucleophilic aromatic substitu-
tion, transition-metal-catalyzed cross-coupling and copper-
catalyzed cycloaddition to azides (click chemistry). The spec-
tral properties of the starting and final difluoroboron dipyrro-
methenes are discussed as a function of their structure.
We now continue this research starting from reactive
monohalogenated BODIPY derivatives that can be pre-
pared in a modular way.[14] Advantages associated with the
synthesis of these dyes are full control of the resulting prop-
erties, and alleviation of the need for double substitution.
A detailed description of the synthesis and substitution of
such monohalogenated BODIPY dyes, as well as an evalu-
ation of the spectroscopic properties as a function of the
dye structure are reported in this paper.
Introduction
The last decade has seen a tremendous rise in the number
of research papers concerning derivatives of 4,4-difluoro-4-
bora-3a,4a-diaza-s-indacene, commonly known as BOD-
IPY.[1] This class of boron-containing heterocycles has
earned a prominent place among fluorescent dyes due to its
excellent properties, such as large molar absorption coeffi-
cients, ε, and relatively high fluorescence quantum yields,
Φf, resulting in high brightness, enhanced stability against
chemicals and light, and absorption and fluorescence emis-
sion spectra located clearly in the visible spectrum
(Ն500 nm).[2]
Results and Discussion
Perhaps the most striking aspect of this recent research
is the development of a rich and sometimes surprising
chemistry, creating a huge functionalization potential for
these fascinating compounds, and leading to dyes with tun-
able spectral characteristics.[2] Among the various synthetic
strategies available for the modification of the BODIPY
core are electrophilic substitutions,[3] condensation reac-
tions,[4] substitution of the fluorine atoms,[5] direct substitu-
tion of the hydrogen atoms,[6] and transition-metal-cata-
lyzed reactions through the use of halogenated systems.[7]
In the context of such halogenated fluorophores, our
group described the synthesis and reactivity of 3,5-dichlor-
inated BODIPYs.[8] These dyes are excellent substrates for
SNAr as well as transition-metal-catalyzed reactions.[8,9]
Moreover, the newly introduced substituents may have a
large effect on the spectroscopic properties.[10] This ap-
proach has caught the attention of several other research
groups, and 3,5-dihalogenated BODIPYs have now found
applications in the synthesis of fluorescent sensors,[11] fluo-
rescent conjugated polymers,[12] and labels for proteins.[13]
Synthesis
The modular condensation approach requires the selec-
tive synthesis of halogenated acylpyrroles. Key starting
compounds, 5-halogenated 2-acylpyrroles 1, are available
from acylation of halogenated pyrrole and, in the initial
procedure, pyrrole was halogenated using N-chlorosuc-
cinimide (NCS).[14,15] Even though this procedure is effec-
tive, substantial variations in yields and reaction times were
observed, mostly due to incomplete halogenation. There-
fore, the halogenation procedure was optimized further and
the use of neat sulfuryl chloride rather than NCS proved to
be a facile and reproducible method.
As reported earlier, condensation of the halogenated
acylpyrrole 1 with another pyrrole moiety 2 leads to forma-
tion of the dipyrrin intermediate 3, which is complexed to
afford the BODIPY fluorophore.[14] This condensation is
efficiently realized by adding phosphorus oxychloride to a
mixture of the pyrroles in dichloromethane, and a range of
BODIPY dyes can be obtained in this fashion from a one-
pot procedure in excellent to moderate yields (Scheme 1).
Particularly, in the case of 2-arylated pyrroles 4e–g, the low-
ered yields can be attributed to scrambling and formation
of the symmetric products. In these cases, it appears crucial
[a] Department of Chemistry, Katholieke Universiteit Leuven,
Celestijnenlaan 200f – bus 02404, 3001 Leuven, Belgium
Fax: +32-16-327990
E-mail: wim.dehaen@chem.kuleuven.be
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200900324.
4386
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Monohalogenated BODIPY Dye Analogues
to use fresh phosphorus oxychloride, and to precipitate the at the 3-position, and this is reflected in its reactivity
intermediate dipyrrinium salt by using an apolar cosolvent towards nucleophiles. Whereas monosubstitution of 3,5-
to obtain good yields.
dichloro-BODIPY dyes with a wide range of nucleophiles
readily takes place at room temperature,[8] in the case of
monochlorinated BODIPYs, all nucleophilic substitutions
need heating for the reactions to proceed at an acceptable
rate (Scheme 3). The reactions are clean and high yielding
in the case of sulfur and nitrogen nucleophiles 8a–c, but in
the case of oxygen nucleophiles, no reaction took place.
This contrasts with previous results on the 3,5-dichlorinated
dyes, where oxygen substitution was very fast, especially
with phenols.[18] Adaptation of the literature procedure re-
garding the base, solvents, and general conditions used, was
unsuccessful. The phenol ether 8d was finally isolated in
moderate yield from a copper-catalyzed Ullman-type
etherification.[19]
Scheme 1. Synthesis of 3-chloro-BODIPY dyes.
Clearly, the position of the halogen atom on the
BODIPY dye depends on the selection of suitably haloge-
nated acylpyrroles. Preparation of constitutional isomers
would thus only require the selection of the correct building
blocks. The 4-halogenated 2-acylpyrrole isomers 6 can be
prepared by halogenation of an intermediate imminium salt
in the acylation of pyrrole.[16] Interestingly, we also found a
fast, highly selective and high yielding synthesis of 4-halo-
genated acetylpyrrole from 2-acetylpyrrole, by using oxone
and sodium halide in methanol/water mixtures
(Scheme 2).[17] This result contrasts with the reported regi-
ochemistry of this reaction.[17] It was observed that cou-
Scheme 3. Substitution of 3-chloro-BODIPY 4b with heteroatom-
containing nucleophiles [CuTC = copper(I)-thiophene-2-carboxyl-
ate].
1
pling constants recorded in the H NMR spectra of these
This copper-catalyzed reaction suggests that the applica-
tion of transition-metal-catalyzed coupling reactions to
these BODIPY dyes is especially interesting, both from a
synthetic and a spectroscopic point of view.
systems are rather small, which, when combined with meta-
coupling and NH-coupling, complicates the assignment of
the structure (see the Supporting Information).
The 3-chloro-BODIPY dyes 4 can be subjected to palla-
dium-catalyzed cross-coupling reactions (Table 1). Suzuki
and Stille reactions gave dyes in excellent yields under stan-
dard arylation conditions. Whereas Stille reactions tend to
be slightly faster, all reactions are clean, with minimal side-
product formation. The products can be isolated in good
yields after column chromatography. In the Suzuki reaction,
both electron-donating and -withdrawing substituents are
tolerated on the aromatic boronic acid. Both for Suzuki and
Scheme 2. Synthesis of 2-monohalogenated BODIPY dyes.
Again, the 4-halogenated 2-acylpyrroles 6 are converted Stille cross-coupling, heteroaromatic rings proved to be ex-
into the BODIPY dyes 7 in typically fair overall yields by cellent coupling partners, with thiophene- (9e) and furan-
applying the standard condensation–complexation se- substituted (9f) dyes obtained in high yield and with ex-
quence, and the halogen atom can be varied from chlorine tended red-shifted emission.
to bromine to iodine (Scheme 2).
Finding general conditions for the Heck reaction proved
The synthetic procedures used to obtain the monohalog- to be difficult because the reaction was slow and low yield-
enated fluorophores can easily be upscaled, and are rou- ing. After an optimization study, use of the mildly electron-
tinely carried out on a multi-gram scale.
donating ligand trifurylphosphane with the palladium cata-
When compared to the 3,5-dichloro-BODIPY dyes, it is lyst was deemed necessary. In this manner, both styryl- and
clear that the additional methyl substituents on the 3- acrylate-substituted fluorophores could be obtained (9g and
monohalogenated dye 4b result in increased electron density 9h, respectively).
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Table 1. Reactivity of 3-chloro-BODIPY dyes 4a and 4b in palla- ing differences when compared to its 3-chlorinated counter-
dium-catalyzed cross-coupling reactions.
part. Whereas for the 3-halogenated system, five to ten mol-
percent of palladium catalyst is routinely used in order to
obtain acceptable reaction times, the application of these
conditions to the 2-iodinated system only led to hydrode-
halogenation. From an optimization study, it was observed
that conducting the reaction with reduced catalyst loadings
(1 mol-% or below) in a secondary amine solvent afforded
superior yields after very short reaction times. Hence, both
arylated and alkynylated (11a and 11b–d, respectively)
products could be obtained (Scheme 4). All attempts to ex-
tend the optimized procedures for the Heck cross-coupling
and copper-catalyzed etherification to the 2-halogenated
BODIPY dyes failed.
Reaction type
Suzuki[a]
R
RЈ
t [h] Yield [%] Product
Ph
Me
Me
Me
Me
Me
Me
Me
Me
Me
5
3
75
93
49
51
90
74
66
87
93
53
57
46
48
70
9a
9b
9c
9d
9e
9a
9e
9f
4-tBuPh
4-MeO-Ph
4-F-Ph
2-thienyl
Ph
2-thienyl
2-furyl
styrene
6
20
2
4
3
Stille[b]
16
2
4
3
3
3
4
Heck[c]
9g
9h
9i
9j
9k
9l
butyl acrylate Me
styrene
H
Me
Me
Sonogashira[d]
PhCϵC
TMSCϵC
TIPSCϵC[e] Me
[a] Suzuki reaction: 0.1 m, toluene/Na2CO3 aq. (1 m), [Pd(PPh3)4]
(5%), boronic acid (1.3 equiv.), reflux. [b] : Stille reaction: 0.1 m,
1,4-dioxane, [Pd(PPh3)4] (5%), tin reagent (1.3 equiv.), reflux. [c]
Heck reaction: 0.1 m, xylene, [Pd2(dba)3] (5%), Fur3P (10%), al-
kene (1.3 equiv.), Na2CO3 (2 equiv.), 130 °C. [d] Sonogashira reac-
tion: 0.1 m, 1,4-dioxane/iPr2NEt (1:1), [Pd(PPh3)4] (5%), CuI (5%),
alkyne (1.2 equiv.), 100 °C. [e] Sonogashira reaction with N-ethyl-
morpholine as base.
Scheme 4. Reactivity of 2-iodo-BODIPY 7c in palladium-catalyzed
cross-coupling reactions.
These protected alkynes (9k, 9l, 11c, and 11d) are of par-
ticular interest, due to the ever increasing application of
acetylenes as reactive handles, in, for example, click chemis-
try and cross-coupling.[23] In an initial attempt to test the
viability of these reactions, deprotection of the terminal al-
kyne was attempted. Even though tetramethylsilane (TMS)
protected acetylene BODIPY 9k underwent rapid deprotec-
tion with both fluoride and hydroxide under a wide range
of conditions, extensive formation of side products always
occurred. However, finally it was observed that removal of
the triisopropylsilyl (TIPS) group on 9l by treatment with a
tenfold excess of tetrabutylammonium fluoride (TBAF) in
tetrahydrofuran (THF) at room temperature, furnished the
Contrary to a recent report by Atkinson et al.[20] and
attesting to the generality of this procedure, the Heck reac-
tion (Table 1, entry 9i) also proceeded cleanly and in good
yield for the meso-unsubstituted dye 4a under these condi-
tions.
The introduction of alkyne substituents through the
Sonogashira reaction is of particular interest due to the
large redshift and high fluorescence quantum yield associ-
ated with such compounds.[21] Applying standard Sonoga-
shira reaction conditions to the model dye 4b delivered both
the phenylethynyl- (9j) and trimethylsilylethynyl-substituted
(9k) products in moderate yield. The lowered yields were
mainly due to multiple alkyne addition, which has been de-
scribed as a side reaction in the Sonogashira coupling.[22]
Attempts to optimize the yields were unsuccessful until it
was finally observed that a bulkier protecting group led to
improved yields, and the (triisopropylsilyl)acetylene-substi-
tuted BODIPY dye 9l was isolated in good yield after short
reaction times.
These reactions proceed in similar yields with other 3-
halo-BODIPY dyes, and this allows fine-tuning of the spec-
troscopic properties of the dye. For example, the Heck reac-
tion of p-anisyl-substituted dye 4f leads to product 10
(Table 1) in 78% yield, combining two substituents that in-
troduce large bathochromic shifts in absorption and
fluorescence bands.
Scheme 5. Deprotection of acetylene-substituted BODIPY and ap-
plication in copper(I)-catalyzed cycloaddition with methyl azido-
The reactivity of a 2-iodinated BODIPY dye 7c in palla-
dium-catalyzed cross-coupling reactions showed some strik- acetate (TBAF = tetrabutylammonium fluoride).
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Monohalogenated BODIPY Dye Analogues
desired compound 12 as the sole product (Scheme 5). After Table 2. Absorption (λabs) and emission (λem) maxima, Stokes shifts
(Δν) and fluorescence quantum yields Φ of 3-chloro-BODIPY dyes
4 (Scheme 1) in several solvents.
˜
f
an extractive purification of the reaction mixture, the ter-
minal acetylene was obtained in near-quantitative yield.
This observation combines nicely with the improved syn-
thetic availability of the TIPS-protected alkyne 9l.
Subjecting terminal acetylene 12 to the copper(I)-cata-
lyzed cycloaddition with methyl azidoacetate[24] provided
1,4-disubstituted 1,2,3-triazole BODIPY 13 as a highly
crystalline solid with intense fluorescence in solution. Like-
wise, subjecting BODIPY dyes 11c and 11d (with a pro-
tected alkyne on the 2-position) to this reaction sequence
efficiently led to the formation of triazole 15 via acetylene
14.
BODIPY Solvent
λabs [nm] λem [nm] Δν [cm–1]
Φf
˜
4a
4b
4c
4d
4e
4f
MeCN
MeOH
THF
toluene
MeCN
MeOH
THF
toluene
MeCN
MeOH
THF
toluene
MeCN
MeOH
THF
toluene
MeCN
MeOH
THF
toluene
MeCN
MeOH
THF
toluene
MeCN
MeOH
THF
496
498
501
507
488
490
493
499
495
496
499
503
514
515
517
523
519
522
526
532
534
536
542
548
554
555
558
565
509
509
512
517
503
504
506
512
511
512
516
520
527
527
529
534
544
545
550
555
565
564
568
573
568
569
573
578
515
434
429
382
611
567
521
509
633
630
660
650
480
442
439
394
885
808
830
779
1027
926
845
796
445
443
469
398
0.74
0.81
0.77
0.76
0.73
0.76
0.79
0.80
0.015
0.014
0.019
0.031
0.69
0.78
0.81
0.86
0.61
0.85
0.87
0.91
0.92
0.86
0.87
0.93
0.84
0.84
0.84
0.85
Spectroscopic Properties
A major advantage of the modular approach is the pos-
sibility to tune the spectroscopic properties of the resulting
dyes. This systematic variation of the second pyrrole moiety
2 led to the preparation of a small library of reactive chlor-
inated BODIPY dyes, which can be substituted in a highly
versatile manner. This feat paves the way for a study of the
relationship between the structure of the dye and its spec-
troscopic properties. In turn, this study should provide sup-
port for rational chemosensor and label design.
4g
Almost all the reactive 3-chlorinated dyes 4 are highly
fluorescent (Table 2). Upon comparing the meso-substitu-
ents, it is clear that hydrogen and methyl substituents (as in
4a and 4b, respectively) produce compounds with very sim-
ilar properties. The methyl-substituted compound 4b has
slightly blue-shifted absorption and emission spectra, but
both have roughly the same high Φf value. A dramatic de-
crease in Φf is observed when a phenyl substituent is present
at the 8-position (e.g., in 4c). The single methyl substituent
at the 7-position is apparently not sufficient to suppress ro-
tation of the phenyl ring, allowing a very efficient nonradia-
tive pathway of excited-state deactivation.[25]
toluene
using these starting compounds and variations thereof, dyes
with colors from green to red are available for further modi-
fication and labeling purposes.
Locking of the alkyl substituents R3 and R4 in a cyclo-
hexyl ring (4d) results in bathochromic shifts of the absorp-
tion and emission maxima of less than 20 nm compared
with 4b, while retaining high Φf.
Aryl substituents at the 5-position (as in 4e and 4f) ex-
tend the conjugated system, and this is reflected in red-
shifted absorption and emission maxima compared with
4a–c, which have methyl substituents at the 5-position. As
the effect is more pronounced in emission, these com-
pounds have enlarged Stokes shifts. The introduction of an
electron-donating methoxy substituent in 4f leads to a fur-
ther increase of the Stokes shift compared with the phenyl-
substituted dye 4e.
Figure 1. Absorption and emission profiles of several 3-chloro-8-
methyl-BODIPY dyes 4 in toluene [4b (squares), 4d (circles), 4e
(stars), 4f (triangles), and 4g (pentagons)]. The spectra are normal-
ized at their respective maxima.
Conformational restriction of the aryl groups in 4g leads
to improved conjugation, resulting in very small Stokes
With the notable exception of oxygen, the location of
shifts and large red-shifts of the absorption and emission heteroatoms at the 3,5-positions has been shown to change
maxima compared with classical BODIPY derivatives.[26]
the spectral properties of the resulting BODIPY derivatives
The absorption and emission profiles of the 3-chloro-8- profoundly.[10] As described previously, oxygen substituents
methyl-BODIPY dyes 4 as a function of their 5,6,7-substit- tethered at the 3-positions do not lead to the bathochromic
uents cover nearly the whole visible spectrum (Figure 1). By shifts observed for other (i.e., S, N) nucleophiles
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(Table 3).[18] Compared with the starting compound 4b, the Table 4. Absorption (λabs) and emission (λem) maxima, Stokes shifts
(Δν) and fluorescence quantum yields Φ of the products 9 from
palladium-catalyzed functionalization (Scheme 4) in several sol-
vents.
˜
f
redshifts of the absorption and emission maxima of 8d re-
main limited to a maximum of 9 nm, whereas the Stokes
shifts and quantum yields are virtually unchanged.
BODIPY
Solvent
λabs [nm] λem [nm] Δν [cm–1]
Φf
˜
9a
MeCN
MeOH
THF
toluene
MeCN
MeOH
THF
toluene
MeCN
MeOH
THF
toluene
MeCN
MeOH
THF
toluene
MeCN
MeOH
THF
toluene
MeCN
MeOH
THF
toluene
MeCN
MeOH
THF
toluene
MeCN
MeOH
THF
507
511
513
521
513
517
522
527
520
528
529
535
507
510
515
520
537
541
547
554
542
545
549
556
548
549
554
559
525
527
531
536
588
591
596
603
538
540
544
548
543
545
549
553
558
560
565
565
538
539
543
546
562
562
566
570
565
567
569
573
562
564
567
571
540
541
543
548
618
619
624
627
1137
1051
1111
946
1077
994
0.94
0.77
0.93
0.85
0.85
0.79
0.86
0.83
0.78
0.85
0.90
0.98
0.50
0.64
0.70
0.61
0.82
0.86
0.81
0.84
0.83
0.82
0.86
0.85
0.81
0.89
0.86
0.85
0.56
0.93
0.89
0.85
0.67
0.56
0.67
0.84
Table 3. Absorption (λabs) and emission (λem) maxima, Stokes shifts
(Δν) and fluorescence quantum yields Φ of the products 8 from
˜
f
nucleophilic substitution (Scheme 3) in several solvents.
9b
9c
9d
9e
9f
BODIPY Solvent λabs [nm]
λem [nm] Δν [cm–1]
Φf
˜
8b
8c
8d
MeCN
MeOH
THF
toluene
MeCN
MeOH
THF
toluene
MeCN
MeOH
THF
525
527
530
536
508
510
514
522
497
499
501
506
544
545
549
553
540
538
543
546
511
512
515
519
665
627
653
574
1167
1020
1039
842
551
509
543
495
0.83
0.86
0.88
0.88
0.64
0.62
0.69
0.73
0.67
0.70
0.75
0.72
942
892
1310
1227
1169
1024
1137
1055
1001
916
828
691
614
507
751
712
640
534
455
484
414
376
529
491
416
409
826
765
753
635
toluene
In comparison to 4b, the introduction of a nitrogen nu-
cleophile in 8c produces large bathochromic shifts of the
absorption (ca. 20 nm) and emission (ca. 35 nm) maxima,
leading to rather large Stokes shifts. The relatively high Φf
values are in line with similar 3-amino-substituted BODIP-
Ys.[13a] Unlike aniline-substituted BODIPY dyes,[10a] the
quantum yield of fluorescence is only slightly solvent de-
pendent. This indicates that there is no substantial charge-
or electron-transfer from the amine to the electron-poor
BODIPY core in the excited state.
For sulfur-substituted 8b, larger λabs combined with λem
similar to those of 8c result in smaller Stokes shift for 8b.
As was observed in previous studies, the sulfide dyes have
very high Φf values.[10b]
9g
9h
10
toluene
MeCN
MeOH
THF
toluene
The exchange of Cl in 4a and 4b for new substituents
through palladium-catalyzed reactions (Scheme 4) leads to
Alkenyl-BODIPY dyes 9g and 9h are also highly fluores-
dyes 9 with bathochromically shifted absorption and emis- cent. The extended conjugation of styrene derivative 9g
sion spectra (Table 4). compared with acrylate 9h leads to an extra bathochromic
With 3-[4-(tert-butyl)]phenyl-BODIPY 9b as the stan- shift of 22–24 nm.
dard, it is clear that the 4-fluorophenyl substituent at the 3-
Having established synthetic routes to both the 2- and 3-
position in 9d has only a minor effect. The electron-with- substituted isomers, a unique opportunity was available to
drawing substituent shifts λabs and λem slightly hypsochrom- compare them spectroscopically. Functionalization at these
ically, and Φf is somewhat reduced, although the compound different positions may well have distinct effects on their
remains highly fluorescent.
spectroscopic properties. Therefore, we made a preliminary
As shown for dye 4f, the electron-donating p-anisyl sub- comparison (Table 5) using the constitutional isomers 9j
stituent induces bathochromic shifts of the absorption and and 11b with phenylacetylene groups, and 13 and 15
emission maxima (Table 2). This is also the case for 9c. The (Scheme 5) with triazole groups. An extensive, detailed
electron-rich five-membered rings thiophene and furan (in spectroscopic and photophysical investigation of several 2-
9e and 9f) bring about red shifts, but result in small Stokes and 3-substituted BODIPY isomers will be published sepa-
shifts when compared with phenylated compounds 9b–d. rately.
These interesting properties, combined with the fact that
When comparing the absorption and emission profiles of
the five-membered heterocycles can be introduced in very the isomeric products 9j and 11b, it is immediately clear
high yield, make them excellent candidates for designing that the two isomers behave quite differently. The 2-alkynyl
and developing fluorescent chelators and indicators, fluo- isomer 11b absorbs at shorter wavelengths (maximum be-
rescent labels for biomolecules, and fluorescent lipophilic tween 504 and 520 nm) than the 3-alkynyl isomer 9j (max-
and membrane probes.
ima in the 525–542 nm range), but nonetheless emits at
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Monohalogenated BODIPY Dye Analogues
Table 5. Absorption (λabs) and emission (λem) maxima, Stokes shifts
(Δν) and fluorescence quantum yields Φ of isomers 11b and 9j (see
˜
f
structures), and 13 and 15 (Scheme 5) in several solvents.
BODIPY Solvent λabs [nm] λem [nm] Δν [cm–1]
Φf
˜
9j
MeCN
MeOH
THF
toluene
MeCN
MeOH
THF
toluene
MeCN
MeOH
THF
toluene
MeCN
MeOH
THF
525
530
535
542
504
508
513
520
522
520
530
535
504
503
517
520
546
548
552
556
571
566
566
562
536
536
543
547
559
554
558
551
733
620
576
0.77
0.85
0.93
0.93
0.25
0.37
0.50
0.61
0.81
0.84
0.92
0.92
0.60
0.53
0.89
0.96
465
11b
13
15
2328
2017
1825
1437
500
574
452
Figure 2. Absorption and emission spectra of 13 (full) and 15
(dashed) (Scheme 5) in toluene. The spectra are normalized at their
respective maxima.
410
with their lower quantum yields, the respective maximal
brightness values of the 2-alkynyl isomer 11b are signifi-
cantly reduced compared with the 3-alkynyl isomer,
amounting to 18400 Lmol–1 cm–1 in chloroform and
11000 Lmol–1 cm–1 in methanol. The full width at half of
the maximum of the absorption band (fwhmabs) of the 3-
alkynyl isomer 9j is about half that of the 2-alkynyl isomer
11b [average fwhmabs = (1.298Ϯ0.202)ϫ 103 cm–1 for 9j
and (2.182Ϯ0.094)ϫ 103 cm–1 for 11b]. A similar trend is
observed for the full width at half of the maximum of the
1952
1830
1421
1082
toluene
longer wavelengths (562–571 nm for 11b, compared with
546–556 nm for 9j) in the solvents tested. Thus, the Stokes
shift is three times larger for the 2-alkynyl isomer [average
Δν = (1.9Ϯ0.4)ϫ 103 cm–1 for 11b vs. (6Ϯ1)ϫ 102 cm–1
˜
emission
band
(fwhmem
)
[average
fwhmem
=
for 9j]. Similar differences were found between 2-triazolyl
derivative 15 and its 3-triazolyl isomer 13. Again, the ab-
sorption spectra of 2-substituted isomer 15 are blue shifted
with respect to those of 13 (maxima between 503 and
520 nm for 15 vs. 520–535 nm for 13). Conversely, the fluo-
rescence emission spectra of 15 are bathochromically
shifted compared with those of 13 (maxima in the 551–
559 nm range for 15 and 536–547 nm for 13), resulting in
three times larger Stokes shifts for 2-substituted isomer 15
(1.103Ϯ0.087)ϫ 103 cm–1 for 9j and (1.842Ϯ0.155)ϫ
103 cm–1 for 11b].
These data demonstrate that 3-substitution is beneficial
for producing BODIPY dyes with sharp absorption bands
and high brightness owing to the large εmax and Φf values.
Maximal Stokes shifts are, however, obtained with 2-substi-
tuted BODIPY dyes.
[average Δν = (1.6Ϯ0.4)ϫ 103 cm–1 for 15 vs. (4.8Ϯ0.7)ϫ
˜
Conclusions
102 cm–1 for 13]. Figure 2 displays the normalized absorp-
tion and fluorescence emission spectra of 13 and 15 in tolu-
Through the identification of synthetic routes to selec-
ene solution. A study of the quantum yields Φf of 9j and tively halogenated pyrroles, a highly versatile modular syn-
11b shows that the 3-alkynyl isomer 9j has higher Φf values thetic route to halogenated BODIPY dyes has been devel-
(0.77–0.93) than 2-alkynyl isomer 11b (0.25–0.61) in the oped. The spectral properties of these dyes can be modified
four solvents studied. Similarly, Φf values of 3-triazolyl iso- through a judicious choice of the second pyrrole moiety.
mer 13 are generally higher (0.81–0.92) than for 2-triazolyl The reactivity of the fluorophores has been thoroughly in-
isomer 15 (0.53–0.96).
vestigated, and is shown to be remarkably flexible. Combin-
The molar absorption coefficient, ε, of the 3-alkynyl iso- ing both the adaptable synthesis and functionalization, dyes
mer 9j is (49.3Ϯ0.2)ϫ 103 Lmol–1 cm–1 in methanol and with absorption and emission spectra tunable throughout
(58.9Ϯ0.9)ϫ 103 Lmol–1 cm–1 in chloroform. With bright- the visible spectrum can be obtained. Optimized procedures
ness defined as the product εϫ Φf,[27] this results in maxi- for the preparation of terminal acetylene-substituted BOD-
mal brightness values of 41900 Lmol–1 cm–1 and IPY and the subsequent copper(I)-catalyzed cycloaddition
47100 Lmol–1 cm–1 in methanol and chloroform, respec- to an azide provide an opportunity for the rapid ligation
tively, for ε = εmax at the absorption maximum. For the 2- of various biological and supramolecular systems with the
alkynyl isomer 11b, εmax values are lower, namely described reactive dyes. Based upon the ease of synthesis
(30.2Ϯ0.2)ϫ 103 Lmol–1 cm–1 in chloroform and and the possibilities for custom-made modification, the
(29.74Ϯ0.05)ϫ 103 Lmol–1 cm–1 in methanol. Combined monohalogenated BODIPY dyes appear to be a privileged
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4391

W. Dehaen et al.
FULL PAPER
heated to reflux for 30 min. The mixture was extracted with diethyl
ether (3ϫ100 mL), washed with saturated NaHCO3 (2ϫ200 mL
or until basic) and water (2ϫ300 mL or until neutral). The solu-
tion was dried with MgSO4, filtered, and evaporated under reduced
pressure until dry. The residue was purified by flash chromatog-
raphy (silica; CH2Cl2/ethyl acetate; 95:5, v/v) to yield the target
pyrrole as a colorless crystalline solid.
system for the design of fluorescent probes and tags. The
reported study of the spectroscopic properties as a function
of the substitution pattern should greatly facilitate the ratio-
nal design of novel fluorescent probes based on the BOD-
IPY platform.
Note: The acylating agent can be prepared for the Vilsmeier reac-
tion by mixing either dimethylamide or N-morpholinoylamide
(22 mmol) and POCl3 (22 mmol) at 0 °C and stirring at room tem-
perature until the Vilsmeier reagent formed. After formation of the
salt, it was dissolved in CH2Cl2 (50 mL) prior to addition.
Experimental Section
General: Chemicals were purchased from Acros Organics, and were
used as received. All reactions were carried out in flame-dried
glassware, but no special precautions were taken to exclude moist-
ure. Solvents were not dried prior to use.
In the case of trichloroacetylation and trifluoroacetylation, the
acylating agent consisted of either trichloroacetyl chloride or tri-
fluoroacetic acid anhydride (20 mmol), respectively, in THF
(50 mL). The hydrolysis could then be replaced by stirring with
water/NaHCO3.
1H and 13C NMR spectra were recorded at room temperature with
a Bruker Avance 300 instrument operating at a frequency of
300 MHz for 1H and 75 MHz for 13C nuclei. In the case of ambigu-
ous assignments, spectra were also run with a Bruker 400 or Bruker
600 spectrometer. 1H NMR spectra in CDCl3 were referenced to
tetramethylsilane (δ =0.00 ppm) as an internal standard. 13C NMR
spectra in CDCl3 were referenced to the CDCl3 (δ = 77.16 ppm)
signal. Mass spectra were recorded on a Hewlett–Packard 5989A
mass spectrometer (EI and CI modes). High-resolution mass data
were obtained with a Kratos MS50TC instrument. Melting points
were taken with a Reichert Thermovar instrument and are uncor-
rected. Microwave irradiation experiments were carried out with a
dedicated CEM-Discover mono-mode microwave apparatus, op-
erating at a frequency of 2.45 GHz with continuous irradiation
power from 0 to 300 W.
5-Chloropyrrole-2-carbaldehyde: Using the general procedure, the
1
compound was isolated as white crystals (1.010 g, 39% yield). H
NMR (CDCl3, 400 MHz): δ = 10.89 (br. s, 1 H, NH), 9.37 (s, 1 H),
6.95 (q, J = 2.76, 3.52 Hz, 1 H), 6.22 (q, J = 2.28, 3.76 Hz, 1
H) ppm. 13C NMR (75 MHz): δ = 178.5, 131.8, 126.5, 123.0,
110.1 ppm. LRMS (EI, 70 eV): m/z = 128. HRMS: calcd. for
C5H4ClNO 128.9981; found 128.9976. Data in full accordance with
literature data.[1]
2-Benzoyl-5-chloropyrrole: Using the general procedure, the com-
pound was isolated as white crystals (10 mmol scale, 670 mg, 33%
1
yield). H NMR (300 MHz): δ = 10.49 (br. s, 1 H, NH), 7.89 (d, J
= 7.29 Hz, 2 H), 7.60 (t, J = 7.32 Hz, 1 H), 7.48 (t, J = 7.29 Hz, 2
Absorption spectra where recorded with a Perkin–Elmer Lambda
40 spectrometer. For the corrected steady-state emission spectra, a
SPEX Fluorolog spectrometer was used. Freshly prepared samples
in 1-cm quartz cells were used for all UV/Vis absorption and emis-
sion measurements. For the determination of the relative fluores-
cence quantum yields (Φf) in solution, only dilute solutions with
an absorbance below 0.1 at the excitation wavelength were used.
Rhodamine 6G (Φf = 0.95) in spectrograde ethanol (Fluka), acri-
dine yellow (Φf = 0.47) in spectrograde ethanol and cresyl violet
(Φf = 0.54) in spectrograde ethanol were used as standards to deter-
mine the fluorescence quantum yields. All spectroscopic measure-
ments were performed at 20 °C.
H), 6.82 (d, J = 2.76 Hz, 1 H), 6.20 (d, J = 3.66 Hz, 1 H) ppm. 13
C
NMR (75 MHz): δ = 184.0, 137.7, 132.2, 130.4, 129.1, 128.5, 124.4,
120.7, 109.6 ppm. LRMS (EI, 70 eV): m/z = 205. Data in full ac-
cordance with literature data.[2]
5-Chloro-2-(trifluoroacetyl)pyrrole: Using the general procedure,
the compound was isolated as white crystals (2.509 g, 64% yield).
1H NMR (300 MHz): δ = 9.81 (br. s, 1 H, NH), 7.17 (m, 1 H), 6.30
(m, 1 H) ppm. 13C NMR (75 MHz): δ = 169.6, 128.6, 125.2, 123.0,
122.9, 118.7, 114.9, 111.5 ppm. LRMS (EI, 70 eV): m/z = 197.
HRMS: calcd for C6H3ClF3NO 196.9855; found 196.98663.
5-Chloro-2-(trichloroacetyl)pyrrole: Using the general procedure
from 2-chloropyrrole and trichloroacetyl chloride, the compound
was isolated as white crystals (2.54 g, 52% yield). CAUTION: The
compound is not stable in solution, and should be stored under
refrigeration; m.p. 79–81 °C. 1H NMR (CDCl3, 400 MHz): δ = 9.56
(br. s, 1 H, NH), 7.33 (t, J = 1.76 Hz, 1 H), 6.25 (t, J = 2 Hz, 1
H) ppm. 13C NMR (75 MHz): δ = 172.4, 125.8, 122.4, 122.3, 110.6,
94.5 ppm. LRMS (EI, 70 eV): m/z = 244.
Synthetic details for compounds 7a–c, 9b, 9j and 9k were reported
by Leen et al.[14a]
General Synthesis of 5-Chloro-2-acylpyrroles
2-Acetyl-5-chloropyrrole: CAUTION: This synthesis describes the
preparation and handling of halogenated pyrroles. These com-
pounds are highly unstable and can decompose rapidly and viol-
ently with the evolution of toxic gases. Always handle these com-
pounds in a fume hood. Any remaining halopyrrole after reaction
can be stabilized by the addition of a few drops of triethylamine to
the reaction mixture just before evaporation.
Condensation Reaction of Selected Pyrroles to the Corresponding
BODIPY
3-Chloro-4,4-difluoro-5,7,8-trimethyl-4-bora-3a,4a-diaza-s-indacene
(4b): 2-Acetyl-5-chloropyrrole (5 mmol, 670 mg) was dissolved in a
mixture of CH2Cl2 (4 mL) and pentane (2 mL) and stirred under
nitrogen. 2,4-Dimethylpyrrole (620 μL, 5 mmol, 1 equiv.) was
added and the resulting solution was cooled to 0 °C in an ice bath,
followed by the addition of POCl3 (470 μL, 5 mmol, 1 equiv.). The
solution was stirred at room temperature for 6 h (during this period
the mixture became dark). Triethylamine (7 mL, 50 mmol) was
added and the mixture was stirred for 10 min. while being cooled
to 0 °C. Boron trifluoride–diethyl ether (7 mL, 55 mmol) was added
dropwise and the reaction mixture was than stirred at room tem-
A stirred solution of pyrrole (1.34 g, 1.4 mL, 20 mmol) in anhy-
drous THF (100 mL) under nitrogen was cooled to –78 °C, and
sulfuryl chloride (2.70 g, 20 mmol) was added dropwise (gas evol-
ution was observed). The resulting solution was stirred at –78 °C
for 3 h, then the acylating agent (see below) was added in a drop-
wise manner over 10 min. and the resulting solution was stirred at
room temperature for 14 h. For Vilsmeier acylations, the mixture
was heated to reflux for 15 min. An aqueous solution of Na2CO3
[100 mmol in H2O (200 mL)] was added and the reaction was
4392
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Eur. J. Org. Chem. 2011, 4386–4396

Monohalogenated BODIPY Dye Analogues
perature for 1 h. The orange solution was poured into diethyl ether
3-Butylamino-5,7,8-trimethyl-4,4-difluoro-4-bora-3a,4a-diaza-s-ind-
(400 mL) and extracted with water (3ϫ200 mL). The organic layer acene (8c): Obtained according to the general nucleophilic substitu-
was dried with MgSO4, filtered, and concentrated in vacuo. The
product was purified by flash column chromatography (silica;
CH2Cl2/petroleum ether; 1:1, v/v) to yield brick-red crystals
(964 mg, 72%); m.p. 228–230 °C. 1H NMR (300 MHz): δ = 7.03
(d, J = 3.63 Hz, 1 H), 6.29 (d, J = 3.66 Hz, 1 H), 6.17 (s, 1 H),
tion procedure, after purification by column chromatography (sil-
ica; CH2Cl2/petroleum ether, 1:1, v/v). Orange solid (no crystals
obtained). 1H NMR (300 MHz): δ = 7.19 (d, J = 4.76 Hz, 1 H),
5.98 (d, J = 4.8 Hz, 1 H), 5.89 (m, 2 H, CH coinciding with NH),
3.32 (q, J = 6.8 Hz, 2 H), 2.44 (s, 3 H), 2.38 (s, 3 H), 2.34 (s, 3 H),
2.58 (s, 3 H), 2.50 (s, 3 H), 2.40 (s, 3 H) ppm. 13C NMR (75 MHz): 1.64 (m, 2 H), 1.46 (m, 2 H), 0.94 (t, J = 7.28 Hz, 3 H) ppm. 13C
δ = 160.8, 145.6, 140.3, 137.3, 134.2, 133.3, 124.0, 123.4, 115.3,
16.9, 15.8, 15.0 ppm. LRMS (EI, 70 eV): m/z = 268 (100) [M]+.
HRMS: calcd. for C12H12BClF2N2 268.07501; found 268.07482.
NMR (75 MHz): δ = 159.9, 144.7, 133.0, 132.0, 131.3, 130.6, 129.6,
117.6, 106.4, 44.2, 32.2, 19.9, 16.0, 15.7, 14.0, 13.8 ppm. MS (EI,
70 eV): m/z = 305. HRMS: calcd. for C16H22N3BF2 305.1875;
found 305.18858.
3-Chloro-4,4-difluoro-5-(4-methoxyphenyl)-4-bora-3a,4a-diaza-s-ind-
acene (4f): Obtained according to the general condensation pro-
cedure in 35 % yield, as a purple solid; m.p. 164 °C. 1H NMR
(300 MHz): δ = 7.92 (d, J = 6.67 Hz, 2 H), 7.34 (d, J = 4.17 Hz, 1
H), 7.19 (d, J = 3.78 Hz, 1 H), 6.99 (d, J = 8.67 Hz, 2 H), 6.69 (d,
J = 3.96 Hz, 1 H), 6.34 (d, J = 3.78 Hz, 1 H), 3.86 (s, 3 H), 2.53
(s, 3 H) ppm. 13C NMR (75 MHz): δ = 161.3, 160.6, 140.4, 140.0,
137.5, 133.5, 131.3, 125.4, 124.4, 121.3, 116.8, 1147.0, 55.4,
15.4 ppm. MS (EI, 70 eV): m/z (%) = 346. HRMS: calcd. for
C17H14BClF2N2O 346.0855; found 346.0866.
4,4-Difluoro-5,7,8-trimethyl-3-phenoxy-4-bora-3a,4a-diaza-s-ind-
acene (8d): BODIPY 4b (27 mg, 0.1 mmol) was dissolved in THF
(1 mL) and degassed by stirring under nitrogen. Copper(I) thio-
phene-2-carboxylate (3.8 mg, 20%), K3PO4 (0.2 mmol, 42 mg), and
phenol (12.2 mg, 1.3 equiv.) were added and the resulting mixture
was stirred at reflux for 6 h. The solvent was removed in vacuo and
the crude product was purified by column chromatography (silica;
CH2Cl2/petroleum ether, 1:1, v/v, then in a second column, diethyl
ether/petroleum ether, 1:2, v/v). Orange solid; m.p. 90 °C. 1H NMR
(300 MHz): δ = 7.42 (t, J = 7.92 Hz, 1 H), 7.28 (m, 4 H), 7.10 (d,
J = 4.05 Hz, 1 H), 6.08 (s, 1 H), 5.64 (d, J = 4.35 Hz, 1 H), 2.55
(s, 3 H), 2.49 (s, 3 H), 2.41 (s, 3 H) ppm. LRMS (EI, 70 EV): m/z =
326. HRMS: calcd. for C18H17BF2N2O 326.1402; found 326.13891.
Naphtho-Fused 3-Chloro-4,4-difluoro-8-methyl-4-bora-3a,4a-diaza-
s-indacene 4g: Obtained according to the general condensation pro-
1
cedure in 30% yield, as a dark shiny solid; m.p. 185 °C. H NMR
(CDCl3, 400 MHz): δ = 8.73 (d, J = 7.28 Hz, 1 H), 7.40–7.25 (m,
5 H), 6.31 (s, 1 H), 2.89 (m, 2 H), 2.72 (m, 2 H), 2.46 (s, 3 H) ppm.
13C NMR (CDCl3, 100 MHz): δ = 155.7, 141.3, 138.7, 137.6, 137.3,
134.2, 133.5, 130.9, 129.1, 129.0, 128.9, 128.5, 127.7, 127.5, 124.8,
124.2, 116.2, 30.4, 22.4, 15.4 ppm. LRMS (EI, 70 EV): m/z = 342.
HRMS: calcd. for C18H14BClF2N2 342.0907; found 342.09103.
General Procedure for the Suzuki Coupling
4,4-Difluoro-5,7,8-trimethyl-3-phenyl-4-bora-3a,4a-diaza-s-indacene
(9a): 3-Chloro-5,7,8-trimethyl-BODIPY 4b (27 mg, 0.1 mmol) was
dissolved in toluene/aqueous Na2CO3 (1 m), and degassed. Phen-
ylboronic acid (16 mg, 0.13 mmol, 1.3 equiv.) and [Pd(PPh3)4]
(11 mg, 0.1 mmol, 10 mol-%) were added and the mixture was
flushed with nitrogen. The reaction mixture was heated to reflux
for 5 h, then poured into diethyl ether (200 mL) and extracted with
water. The organic layer was dried with MgSO4, evaporated to dry-
ness, and the crude mixture was purified by flash chromatography
(silica; CH2Cl2/petroleum ether, 1:1 v/v). Dark-red solid; m.p.
General Procedure for the Nucleophilic Aromatic Substitution
4,4-Difluoro-5,7,8-trimethyl-3-phenylsulfenyl-4-bora-3a,4a-diaza-s-
indacene (8a): To a solution of monochlorinated BODIPY 4b
(27 mg, 0.1 mmol) in acetonitrille (1 mL), was added thiophenol
(11.5 μL, 0.11 mmol, 1.1 equiv.) and triethylamine (15.5 μL,
1.1 equiv.). The resulting mixture was stirred at 60 °C until TLC
analysis indicated complete reaction. The reaction mixture was
poured into diethyl ether (100 mL), and the organic layer was
washed with aqueous Na2CO3 (1 m, 100 mL). The organic layer
was combined, dried with MgSO4, filtered, and the solvents evapo-
rated to dryness. The crude solid was purified by column
chromatography (silica; CH2Cl2/petroleum ether, 1:1, v/v) as a red
1
175 °C. H NMR (CDCl3, 400 MHz): δ = 7.85 (d, J = 7.32 Hz, 2
H), 7.45–7.37 (m, 3 H), 7.17 (d, J = 4.28 Hz, 1 H), 6.53 (d, J =
4.28 Hz, 2 H), 6.12 (s, 1 H), 2.57 (s, 3 H), 2.52 (s, 3 H), 2.41 (s, 3
H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 158.7, 154.5, 143.9,
140.9, 136.0, 133.5, 133.4, 129.2 (t), 128.8, 128.2, 125.1, 122.8,
118.0, 16.9, 16.5, 15.1 ppm. LRMS (EI, 70 EV): m/z = 310. HRMS:
calcd. for C18H17BF2N2 310.1453; found 310.14699.
1
solid; m.p. 132 °C. H NMR (300 MHz): δ = 7.57 (m, 2 H), 7.36
General Procedure for Stille Coupling: 3-Chloro-5,7,8-trimethyl-
BODIPY 4b (27 mg, 0.1 mmol) was dissolved in toluene. Tributyl-
phenyltin (47 mg, 42 μL, 0.13 mmol, 1.3 equiv.), [Pd(PPh3)4]
(11 mg, 0.1 mmol, 10 mol-%) and Na2CO3 (16 mg, 0.15 mmol,
1.5 equiv.) were added and the mixture was flushed with nitrogen.
The reaction mixture was heated to reflux for 14 h, followed by
evaporation of the solvent. The crude mixture was purified by flash
chromatography (silica; CH2Cl2/petroleum ether, 1:1 v/v).
(m, 3 H), 6.94 (d, J = 4.32 Hz, 1 H), 6.06 (s, 1 H), 5.64 (d, J =
4.17 Hz, 1 H), 2.54 (s, 3 H), 2.37 (s, 3 H), 2.31 (s, 3 H) ppm. 13C
NMR (CDCl3, 100 MHz): δ = 157.3, 151.7, 142.9, 138.7, 136.0,
134.1, 133.2, 131.6, 129.5, 129.0, 125.0, 122.1, 117.5, 16.7, 16.1,
14.8 ppm. LRMS (EI, 70 EV): m/z = 342. HRMS: calcd. for
C18H17BF2N2S 342.11736; found 342.11688.
3-Butylsulfenyl-5,7,8-trimethyl-4,4-difluoro-4-bora-3a,4a-diaza-s-ind-
acene (8b): Obtained according to the general nucleophilic substitu-
tion procedure, purified by column chromatography (silica; diethyl
ether/petroleum ether, 1:3, v/v). Dark-orange solid; m.p. 95–97 °C.
1H NMR (CDCl3, 400 MHz): δ = 7.11 (d, J = 4.28 Hz, 1 H), 6.34
4,4-Difluoro-3-(4-methoxyphenyl)-5,7,8-trimethyl-4-bora-3a,4a-di-
aza-s-indacene (9c): Obtained according to the general procedure
for Suzuki coupling, and purified by column chromatography (sil-
1
ica; CH2Cl2/petroleum ether, 1:1, v/v). Red solid; m.p. 147 °C. H
(d, J = 4.28 Hz, 1 H), 6.07 (s, 1 H), 3.04 (t, J = 7.32 Hz, 2 H), 2.54 NMR (300 MHz): δ = 7.83 (d, J = 9.12 Hz, 2 H), 7.18 (d, J =
(s, 3 H), 2.47 (s, 3 H), 2.37 (s, 3 H), 1.75 (quint, J = 6.96 Hz, 5 H), 3.66 Hz, 1 H), 6.97 (d, J = 8.22 Hz, 2 H), 6.53 (d, J = 3.63 Hz, 1
1.51 (m, 2 H), 0.94 (t, J = 7.32 Hz, 3 H) ppm. 13C NMR (CDCl3, H), 6.11 (s, 1 H), 3.85 (s, 3 H), 2.57 (s, 3 H), 2.42 (s, 3 H) ppm. 13
C
100 MHz): δ = 156.2, 153.2, 142.0, 127.7, 125.7, 132.8, 125.5, 121.6,
115.0, 32.6, 31.0, 21.9, 16.5, 16.1, 14.6, 13.6 ppm. LRMS (EI, 70
EV): m/z = 322. HRMS: calcd. for C16H21N2SBF2 322.14866;
found 322.14875.
NMR (75 MHz): δ = 160.3, 157.7, 154.9, 143.1, 140.3, 136.1, 133.1,
130.8, 130.7, 130.7, 125.8, 125.5, 122.3, 118.0, 113.7, 55.3, 16.8,
16.5, 15.0 ppm. MS (EI, 70 eV): m/z = 340. HRMS: calcd. for
C19H19BF2N2O 340.1559; found 340.1565.
Eur. J. Org. Chem. 2011, 4386–4396
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W. Dehaen et al.
FULL PAPER
4,4-Difluoro-3-(4-fluorophenyl)-5,7,8-trimethyl-4-bora-3a,4a-diaza-
s-indacene (9d): Obtained according to the general procedure for
Suzuki coupling, and purified by column chromatography (silica;
CH2Cl2/petroleum ether, 1:1, v/v). Orange solid; m.p. 150–152 °C.
1H NMR (400 MHz): δ = 7.84 (q, J = 5.49 Hz, 2 H), 7.18 (d, J =
4.59 Hz, 1 H), 7.12 (t, J = 8.22 Hz, 2 H), 6.49 (d, J = 3.66 Hz, 1
15.2, 13.9 ppm. MS (EI, 70 eV): m/z = 360. HRMS: calcd. for
C19H23BF2N2O2 360.18206; found 360.18217.
4,4-Difluoro-5,7-dimethyl-3-(2-phenylethenyl)-4-bora-3a,4a-diaza-s-
indacene (9i): The compound was obtained according to the general
procedure for the Heck reaction from 4a as a purple solid, in 57%
1
yield; m.p. 184 °C. H NMR (300 MHz): δ = 7.65–7.57 (m, 3 H),
H), 6.14 (s, 1 H), 2.58 (s, 3 H), 2.52 (s, 3 H), 2.42 (s, 3 H) ppm. 13
C
7.38–7.24 (m, 4 H), 7.03 (s, 1 H), 6.63 (d, J = 4.04 Hz, 1 H), 6.84
(d, J = 4.28 Hz, 1 H), 6.10 (s, 1 H), 2.59 (s, 3 H), 2.24 (s, 3 H) ppm.
13C NMR (75 MHz): δ = 159.4, 153.6, 142.8, 136.6, 135.7, 135.4,
135.0, 128.9, 128.8, 128.4, 127.5, 122.1, 120.2, 119.4, 115.3, 15.1,
11.4 ppm. MS (EI, 70 eV): m/z = 322. HRMS: Calcd. for
C19H17BF2N2 322.14529; found 322.14413.
NMR (75 MHz): δ = 164.5, 162.0, 159.1, 153.2, 144.2, 140.9, 136.0,
133.6, 131.2 (q), 129.6 (d), 125.0, 122.9, 117.8, 115.3, 115.1, 16.9,
16.5, 15.1, 15.0 ppm. MS (EI, 70 eV): m/z = 328. HRMS: calcd.
for C18H16N2BF3 328.1359; found 328.13725.
4,4-Difluoro-5,7,8-trimethyl-3-(2-thienyl)-4-bora-3a,4a-diaza-s-ind-
acene (9e): Obtained according to the general procedure for Stille
reaction, and purified by column chromatography (silica; CH2Cl2/
petroleum ether, 1:1, v/v) in 66% yield. Dark solid; m.p. 148 °C.
1H NMR (300 MHz): δ = 8.00 (d, J = 2.73 Hz, 1 H), 7.37 (d, J =
5.46 Hz, 1 H), 7.13–7.09 (m, 2 H), 6.67 (d, J = 3.63 Hz, 1 H), 6.12
(s, 1 H), 2.58 (s, 3 H), 2.50 (s, 3 H), 2.38 (s, 3 H) ppm. 13C NMR
(75 MHz): δ = 158.1, 146.8, 143.4, 139.8, 136.3, 134.7, 133.5, 129.5,
129.4, 127.5, 125.2, 122.6, 118.0, 16.8, 16.4, 15.0 ppm. MS (EI,
70 eV): m/z = 316. HRMS: calcd. for C16H15BF2N2S 316.10171;
found 316.10172.
4,4-Difluoro-3-(4-methoxyphenyl)-8-methyl-5-(2-phenylvinyl)-4-
bora-3a,4a-diaza-s-indacene (10): Obtained according to the general
procedure for Heck coupling after 1 h, and purified by column
chromatography (silica; CH2Cl2/petroleum ether, 1:1, v/v). Dark
1
shiny solid; m.p. 184–186 °C. H NMR (300 MHz): δ = 7.92 (d, J
= 8.85 Hz, 2 H), 7.67 (d, J = 16.38 Hz, 1 H), 7.57 (d, J = 7.14 Hz,
2 H), 7.38–7.21 (m, 6 H), 7.02 (d, J = 8.85 Hz, 2 H), 6.92 (d, J =
4.5 Hz, 1 H), 6.61 (d, J = 4.14 Hz, 1 H), 3.88 (s, 3 H), 2.56 (s, 3
H) ppm. 13C NMR (75 MHz): δ = 160.7, 148.0, 154.9, 138.5, 136.9,
136.4, 131.2, 131.1, 131.0, 129.1, 128.8, 127.7, 127.0, 126.5, 125.4,
119.4, 119.4, 116.2, 113.9, 55.3, 15.5 ppm. MS (EI, 70 eV): m/z =
310. HRMS: calcd. for C18H17N2BF2 310.14529; found 310.14699.
4,4-Difluoro-3-(2-furyl)-5,7,8-trimethyl-4-bora-3a,4a-di-
aza-s-indacene (9f): Obtained according to the general procedure
for Suzuki coupling, and purified by column chromatography (sil-
1
ica; CH2Cl2/petroleum ether, 1:1, v/v). Red solid; m.p. 128 °C. H
4,4-Difluoro-5,7,8-trimethyl-3-[2-(triisopropylsilyl)ethynyl]-4-bora-
3a,4a-diaza-s-indacene (9l): BODIPY 4b (414 mg, 1 mmol) was dis-
solved in dioxane (4 mL) and N-ethylmorpholine (4 mL) and
purged with nitrogen. To the resulting solution was added (triiso-
propylsilyl)acetylene (185 μL, 1.3 mmol, 1.3 equiv.), followed by
tetrakis(triphenylphosphane)palladium (55 mg, 0.05 mmol, 5 mol-
%), and CuI (19 mg, 0.02 mmol, 10 mol-%). The mixture was
stirred at 80 °C for 10 h and cooled to room temperature, then the
solvent was removed. The product was purified by column
chromatography (silica; CH2Cl2/petroleum ether, 1:1, v/v) to yield
9l as a shiny red solid (290 mg, 70 %); m.p. 136 °C. 1H NMR
(300 MHz): δ = 6.97 (d, J = 3.78 Hz, 1 H), 6.5 (d, J = 3.78 Hz, 1
H), 6.15 (s, 1 H), 2.57 (s, 3 H), 2.50 (s, 3 H), 2.39 (s, 3 H), 1.16 (s,
21 H) ppm. 13C NMR (75 MHz): δ = 161.4, 145.3, 139.7, 135.0,
134.8, 131.5, 123.4, 122.8, 121.7, 101.3, 98.9, 18.7, 17.0, 16.3, 15.1,
11.5 ppm. LRMS (EI, 70 eV): m/z = 414. HRMS: calcd. for
C23H33BF2N2Si 414.2474; found 414.24666.
NMR (400 MHz): δ = 7.5 (s, 2 H), 7.12 (d, J = 4.56 Hz, 1 H), 6.87
(d, J = 3.66 Hz, 1 H), 6.55 (d, J = 1.83 Hz, 1 H), 6.11 (s, 1 H),
2.59 (s, 3 H), 2.51 (s, 3 H), 2.38 (s, 3 H) ppm. 13C NMR (75 MHz):
δ = 157.7, 146.9, 143.6, 143.5, 143.2, 139.6, 136.1, 133.5, 125.3,
122.4, 116.2, 113.4, 113.3, 113.2, 113.0, 16.7, 14.9 ppm. MS (EI,
70 eV): m/z = 300. HRMS: calcd. for C16H15BF2N2O 300.12455;
found 300.12388.
General Procedure for the Heck Reaction
4,4-Difluoro-5,7,8-trimethyl-3-(2-phenylethenyl)-4-bora-3a,4a-diaza-
s-indacene (9g): BODIPY 4b (53.6 mg, 0.2 mmol) was dissolved in
xylene (2 mL) and purged with nitrogen. To the resulting solution
was added styrene (30 μL, 0.26 mmol, 1.3 equiv.), followed by
[Pd2(dba)3] (9 mg, 0.01 mmol, 5 mol-%), tri-(2-furyl)phosphane
(2.3 mg, 0.02 mmol, 10 mol-%), and Na2CO3 (42 mg, 0.4 mmol,
2 equiv.). The mixture was stirred at 130 °C under nitrogen in a
closed vial for 3 h and then cooled to room temperature. The sol-
vent was removed and the product was purified by column
chromatography (silica; CH2Cl2/petroleum ether, 1:1, v/v) to yield
4,4-Difluoro-5,7,8-trimethyl-2-phenylethynyl-4-bora-3a,4a-diaza-s-
indacene (11d): 2-Iodo-5,7,8-trimethyl-BODIPY (53.6 mg,
0.2 mmol) was dissolved in iPr2NH (2 mL) and purged with nitro-
gen. To the resulting solution was added (triisopropylsilyl)acetylene
(59 μL, 0.26 mmol, 1.3 equiv.), followed by tetrakis(triphenylphos-
phane)palladium (1.1 mg, 0.002 mmol, 0.5 mol-%), and CuI (1 mg,
0.005 mmol, 2.5 mol-%). The mixture was stirred at 80 °C in a
closed vial for 90 min then cooled to room temperature. The mix-
ture was poured into diethyl ether (100 mL), and extracted with
dilute hydrochloric acid (2ϫ 100 mL, or until acidic), NaHCO3
(2ϫ 100 mL, or until basic), and brine (100 mL). The organic layer
was combined, dried, and the solvent was removed. The product
was purified by column chromatography (silica; CH2Cl2/petroleum
ether, 1:1, v/v) to yield the dye as a bright-red solid; m.p. 136 °C.
1H NMR (300 MHz): δ = 6.97 (d, J = 3.66 Hz, 1 H), 6.55 (d, J =
3.78 Hz, 1 H), 6.15 (s, 1 H), 2.58 (s, 3 H), 2.51 (s, 3 H), 2.40 (s, 3
1
the dye as dark crystals; m.p. 240–243 °C. H NMR (300 MHz): δ
= 7.63 (d, J = 16.3 Hz, 1 H), 7.57 (d, J = 7.32 Hz, 2 H), 7.35 (t, J
= 7.04 Hz, 2 H), 7.28 (d, J = 7.32 Hz, 1 H), 7.28 (s, 1 H), 7.13 (d,
J = 4.28 Hz, 1 H), 6.84 (d, J = 4.28 Hz, 1 H), 6.11 (s, 1 H), 2.59
(s, 3 H), 2.40 (s, 3 H) ppm. 13C NMR (75 MHz): δ = 156.9, 152.3,
142.7, 139.0, 136.8, 135.9, 134.9, 133.3, 129.8, 128.7, 125.7, 121.9,
119.5, 114.5, 16.7, 16.4, 14.9 ppm. MS (EI, 70 eV): m/z = 336.
HRMS: calcd. for C20H19F2N2 336.16094; found 336.16138.
3-[2-Butoxycarbonylvinyl]-4,4-difluoro-4-bora-3a,4a-diaza-s-ind-
acene (9h): Obtained according to the general procedure for Heck
coupling after 4 h, and purified by column chromatography (silica;
CH2Cl2/petroleum ether, 1:1, v/v). Red solid; m.p. 163 °C. 1H NMR
(300 MHz): δ = 8.04 (d, J = 15.99 Hz, 1 H), 7.05 (d, J = 4.14 Hz,
1 H), 6.79 (d, J = 4.32 Hz, 1 H), 6.44 (d, J = 16.17 Hz, 1 H), 6.20
(s, 3 H), 4.21 (t, J = 6.6 Hz, 2 H), 2.60 (s, 3 H), 2.54 (s, 3 H), 2.42 H), 1.17 (s, 21 H) ppm. 13C NMR (75 MHz): δ = 161.4, 145.3,
(s, 3 H), 1.72 (m, 3 H), 1.48 (m, 2 H), 0.96 (t, J = 7.35 Hz, 3 139.7, 135.0, 134.8, 131.5, 123.4, 122.8, 121.7, 101.3, 98.9, 18.7,
H) ppm. 13C NMR (75 MHz): δ = 166.7, 161.5, 146.5, 145.8, 140.3,
17.0, 16.3, 15.1, 11.5 ppm. LRMS (EI, 70 eV): m/z = 141. HRMS:
136.5, 134.9, 134.1, 123.8, 121.6, 115.5, 64.6, 30.8, 19.2, 17.0, 16.3,
Calcd. for C23H33BF2N2Si 414.24740; found 414.24666.
4394
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 4386–4396

Monohalogenated BODIPY Dye Analogues
[3] a) K. Takuma, T. Misawa, K. Sugimoto, T. Nishimoto, H. Tsu-
kahara, T. Tsuda, G. Imai, H. Kogure, 1998, JP Patent
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3-Ethynyl-4,4-difluoro-5,7,8-trimethyl-4-bora-3a,4a-diaza-s-ind-
acene (12): To a solution of TIPS-BODIPY 9l (41 mg, 0.1 mmol)
in THF (2 mL) was added TBAF (1 m in THF, 1 mL 10 equiv.) (the
reaction mixture immediately became transparent), and stirred for
4 h. The mixture was poured into aqueous NH4Cl/diethyl ether and
shaken. The bright fluorescent organic layer was extracted with
water, dried with MgSO4, and the solvents evaporated to dryness.
The red solid obtained was used without further purification, and
should be stored under refrigeration. 1H NMR (300 MHz): δ =
6.98 (d, J = 3.96 Hz, 1 H), 6.61 (d, J = 3.96 Hz, 1 H), 6.21 (s, 1
H), 3.62 (s, 1 H), 2.61 (s, 3 H), 2.54 (s, 3 H), 2.54 (s, 3 H), 2.42 (s,
3 H) ppm. 13C NMR (75 MHz): δ = 162.5, 146.2, 140.1, 134.7,
129.6, 123.9, 122.4, 121.5, 92.2, 84.9, 19.4, 18.7, 16.9 ppm. LRMS
(EI, 70 eV): m/z = 258.
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Methyl 2-[4-(4,4-Difluoro-5,7,8-trimethyl-4-bora-3a,4a-diaza-s-ind-
acen-3-yl)-1,2,3-triazol-1-yl] Acetate (13): Alkynyl-BODIPY 12
(26 mg, 0.1 mmol) was dissolved in THF (1 mL), followed by the
addition of methyl azidoacetate (11.5 mg, 0.1 mmol, 1 equiv.) and
tetrakis acetonitrile copper hexafluorophosphate (38 mg, 0.1 mmol,
1 equiv.), and the mixture was stirred at reflux for 2 h, followed by
evaporation of the solvent. The crude solid was purified by column
chromatography (silica; CH2Cl2/ethyl acetate, 9:1 v/v) to yield the
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1
product as a red crystalline solid; m.p. 230 °C. H NMR (CDCl3,
400 MHz): δ = 8.56 (s, 1 H), 7.28 (d, J = 4.28 Hz, 1 H), 7.21 (d, J
= 4.28 Hz, 1 H), 6.16 (s, 1 H), 5.23 (s, 2 H), 3.81 (s, 3 H), 2.58 (s,
6 H), 2.43 (s, 3 H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 166.6,
158.6, 144.1, 143.7, 140.7, 136.1, 133.7, 125.7, 125.5, 125.4, 122.8,
11.6, 117.3, 53.2, 50.9, 16.9, 16.6, 15.0 ppm. LRMS (EI, 70 EV):
m/z = 373. HRMS: calcd. for C17H18BF2N5O2 373.1522; found
373.15028.
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T. Rohand, W. Qin, N. Boens, W. Dehaen, Eur. J. Org. Chem.
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acen-2-yl)-1,2,3-triazol-1-yl] Acetate (15): Crude alkynyl-BODIPY
14 (26 mg, 0.1 mmol) was dissolved in THF (1 mL), followed by
addition of methyl azidoacetate (11.5 mg, 0.1 mmol, 1 equiv.) and
tetrakis acetonitrile copper hexafluorophosphate (38 mg, 0.1 mmol,
1 equiv.), and the mixture was stirred at reflux for 2 h, followed by
evaporation of the solvent. The crude solid was purified by column
chromatography (silica; CH2Cl2/ethyl acetate, 9:1 v/v) to yield the
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1
product as a red crystalline solid; m.p. 226 °C. H NMR (CDCl3,
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400 MHz): δ = 7.90 (s, 1 H), 7.76 (s, 1 H), 7.50 (s, 1 H), 6.21 (s, 1
H), 5.21 (s, 2 H), 3.83 (s, 3 H), 2.62 (s, 3 H), 2.60 (s, 3 H), 2.45 (s,
3 H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 166.8, 163.4, 161.5,
146.3, 143.9, 143.0, 134.9, 123.4, 121.0, 120.1, 119.7, 53.2, 50.9,
17.1, 16.5, 15.1 ppm. LRMS (EI, 70 EV): m/z = 373. HRMS: calcd.
for C17H18BF2N5O2 373.1522; found 373.15057.
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Supporting Information (see footnote on the first page of this arti-
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a fellowship to V. L. We thank the Fonds voor Wetenschappelijk
Onderzoek, the Ministerie voor Wetenschapsbeleid and the K. U.
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www.eurjoc.org
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Received: March 7, 2011
Published Online: June 21, 2011
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 4386–4396