Synthesis and substitution of 8-(4,6-Dichloropyrimidin-5-yl)-BODIPY

Article abstract of DOI:10.1002/ejoc.200900722

meso-Dichloropyrimidyl-BODIPY dyes are readily substituted by nucleophiles or through palladium-catalysed coupling reactions, while retaining excellent quantum yields of fluorescence.

Full text of DOI:10.1002/ejoc.200900722

FULL PAPER
DOI: 10.1002/ejoc.200900722
Synthesis and Substitution of 8-(4,6-Dichloropyrimidin-5-yl)-BODIPY
Volker Leen,[a] Florian Schevenels,[a] Jie Cui,[b] Chan Xu,[b] Wensheng Yang,[b]
Xiaoliang Tang,[b] Weisheng Liu,[b] Wenwu Qin,[b] Wim M. De Borggraeve,[a] Noël Boens,[a]
and Wim Dehaen*[a]
Keywords: Fluorescent probes / Nucleophilic substitution / Palladium-catalysed reactions / Dyes/pigments
meso-Dichloropyrimidyl-BODIPY dyes are readily substi-
tuted by nucleophiles or through palladium-catalysed cou-
pling reactions, while retaining excellent quantum yields of
fluorescence.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
dye often leads, for example, to decreased fluorescence
quantum yields (Φf) or lowered stabilities.[7a] It can there-
fore be desirable to introduce a functionality that exhibits
similar reactivity, but at the meso-position, where substitu-
tion should have no direct influence on the spectroscopic
properties.
Here we report the synthesis of BODIPY dyes substi-
tuted at their meso-positions with a 4,6-dichloropyrimidine
subunit. This moiety has previously been used by us in sev-
eral research projects and has proved its reactivity towards
nucleophiles and transition-metal-catalysed coupling reac-
tions.[8]
Introduction
Although the 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene
(better known under its commercial name “BODIPY”)
fluorophore has been known since 1968, there has been tre-
mendous growth in research into this interesting dye in re-
cent years.[1] Dyes of this class currently enjoy great popu-
larity because of their photostabilities, relatively high fluo-
rescence quantum yields Φf and molar absorption coeffi-
cients ε(λ).
This recent rise in popularity of the BODIPY fluoro-
phore has sparked research directed towards reactive dyes
for convenient labelling and modification of the dye. Of the
several approaches used, here we mention only those based
on the reactivity of acidic 3,5-methyl groups,[2] sulphide-
substituted dyes[3] and a range of halogenated structures.[4]
In the course of our research we have reported on the
reactivities of 3,5-dihalogenated BODIPY dyes. These
products can be elaborated both by nucleophilic aromatic
Results and Discussion
Synthesis
meso-(4,6-Dichloropyrimidin-5-yl)-BODIPY compounds
substitution,[5] with a wide range of nucleophiles, and by were conveniently prepared by established procedures[1]
palladium-catalysed coupling reactions.[6] The introduction (Figure 1). Starting from commercially available 4,6-dihy-
of these new substituents directly on the fluorescent system droxypyrimidine (1) we were able to obtain the dichlori-
profoundly changes the spectral properties of the fluoro- nated pyrimidinealdehyde 2 in good yield by a previously
phore.[7] Although this can be beneficial for several photo- published procedure.[9] Acid-catalysed condensations of this
physical applications, as well as for the introduction of large aldehyde with the selected pyrroles 3a–d yielded the di-
bathochromic shifts in the UV/Vis absorption and fluores- pyrromethanes 4a–d. The unsubstituted dipyrromethane 4a
cence spectra of the compounds, some drawbacks must also can also be prepared by a previously reported method.[10]
be acknowledged. The introduction of nucleophiles on the This method employs only 3 equiv. of pyrrole and water as
the solvent, in contrast to the standard procedure, in which
pyrrole is the solvent. In the case of an α-substituted-
pyrrole, polycondensation is not an issue, and the commer-
cially available 2,4-dimethylpyrrole (3b) can undergo the
condensation under trifluoroacetic acid (TFA) catalysis
conditions in dichloromethane. The other α-substituted
pyrroles, 3c and 3d, can be obtained through Trofimov reac-
tions, which furnish the pyrroles in single-step fashion with
moderate yields and potential for large-scale reactions.[11]
[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
[b] Key Laboratory of Nonferrous Metal Chemistry and Resources
Utilization of Gansu Province, State Key Laboratory of Ap-
plied Organic Chemistry, College of Chemistry and Chemical
Engineering
Lanzhou University, Lanzhou 730000, P. R. China
5920
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 5920–5926

8-(4,6-Dichloropyrimidin-5-yl)-BODIPY
obtained for substitution with 2-naphthol to afford dye 9.
The crown ether catalyst was not necessary with the sulfur
nucleophile thiophenol 10. Again, use of longer reaction
times and more nucleophile led to the disubstituted product
11. Nitrogen-centred nucleophiles such as aniline and piper-
idine did not react under the conditions described here.
Table 1. Nucleophilic substitutions on 3,5-diphenyl-BODIPY 5c.
Figure 1. Synthesis of 8-(4,6-dichloropyrimidin-5-yl)-BODIPY.
[a] Overall yields from 2.
Product R1
R2
Conditions[a] Time [h] Yield[b]
7
8
8
OPh
OPh
OPh
Cl
OPh
OPh
A
A
B
B
A
A
B
B
A
16
60
4
4
4
40
1
1
98
85
96
75
93
91
93
80
94
These dipyrromethanes 4a–d were then oxidized to the
corresponding dipyrromethenes with DDQ. In a final step,
the dipyrromethenes were complexed with boron trifluoride
by treatment with triethylamine in dichloromethane. These
entire sequences could also be performed in one-pot pro-
cedures with fair to good yields. The desired BODIPY dyes
5a–d can then be purified by flash column chromatography
and crystallization.
9
ONaphth ONaphth
10
11
11
12
13
SPh
SPh
SPh
OPh
OPh
Cl
SPh
SPh
SPh
SMe
20
[a] Conditions: A) room temp., DMF; B) 100 °C, DMF. [b] Isolated
yields for a 0.2 mmol reaction.
Aliphatic oxygen nucleophiles (methoxide and ethoxide)
showed only limited reactivity resulting in sluggish reac-
tions, and no product could be isolated.
We were also able to perform nonsymmetric substitu-
tions by adding a second nucleophile after the completion
of the first substitution, which could be followed by thin-
layer chromatography. Thus, after complete substitution
with phenol, addition of an equivalent of thiophenol or so-
dium thiomethoxide resulted in the nonsymmetrically sub-
stituted dyes 12 and 13.
At room temperature the developed method is very mild,
but takes 16 to 60 hours. Gentle heating of the reaction
mixtures speeded up the reactions and all were complete in
a few hours. Heating to 100 °C also allowed the disubsti-
tuted products to be obtained within acceptable reaction
times. It is noteworthy that the first substitution lowers the
reactivity of the remaining chlorine significantly. In the
presence of 1 equiv. of nucleophile only monosubstituted
product was observed.
Nucleophilic Substitution
We initially applied this protocol to 2,4-dimethylpyrrole
(3b), which resulted in the 1,3,5,7-tetramethyl-substituted
BODIPY 5b. We then treated this compound with several
nucleophiles under a wide range of conditions to test its
reactivity in nucleophilic aromatic substitution. Almost no
reaction could be observed, however, and it was only after
several hours in DMF at elevated temperatures that we were
able to observe substitution by thiophenol. After disappear-
ance of the starting material, only a 15% yield of the mono-
substituted product 6 could be recovered. This might be
caused by steric hindrance by the 1- and 7-methyl groups,
which might disfavour the transition state of the nucleo-
philic attack. To test this hypothesis, we decided to continue
work with the 1,7-unsubstituted compounds 5c and 5d.
With the 3,5-diphenyl dye 5c as a model system, substitu-
tion with several nucleophiles was examined, and immedi-
ate incorporation of these nucleophiles with excellent yields
could be observed (Table 1). Most reactions proceeded with
superb yields, and spectroscopically pure samples could be
obtained after flash column chromatography or recrystalli-
zation. Substitutions with phenol were carried out in DMF
Palladium-Catalysed Reactions
We next turned our attention to palladium-catalysed
with 18-crown-6 as a catalyst, to yield both the monosubsti- coupling reactions (Table 2). On trying to apply the Suzuki
tuted 7 and the disubstituted product 8. Similar yields were protocol under standard conditions we saw very slow reac-
Eur. J. Org. Chem. 2009, 5920–5926
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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5921

W. Dehaen et al.
FULL PAPER
tions, and it was only after several hours at elevated tem- to a strong base with sterically demanding ligands allowed
peratures that coupling began to be observed. To get the us to obtain the aminated dye. Running the reaction under
reactions to acceptable speeds, rather large amounts of cata- the same conditions but with omission of the palladium
lyst had to be used.
catalyst did not yield the product, so we can rule out an
anionic mechanism of nucleophilic substitution by an
amide nucleophile. Unfortunately, but not to our surprise,
the bis-aminated dye remained elusive, due to the very
strong deactivation caused by the first substituent. Long
reaction times under the active conditions only led to
monosubstitution and subsequent decomposition.
Table 2. Palladium-catalysed substitutions on 3,5-diphenyl-BOD-
IPY 5c.[a]
Spectroscopic Properties
Both the unsubstituted and the substituted BODIPY
dyes show spectroscopic properties similar to those of pre-
viously described boron dipyrromethene dyes (i.e., narrow
bands of absorption and emission with small Stokes shifts;
Table 3). There is no significant influence of the substitu-
ents on the spectroscopic characteristics. A small hypsoch-
romic shift of about 10 nm is visible with oxygen-substi-
tuted dyes 8 and 9. With the amine-substituted dye 18, no
strong influence of the amine could be observed. The quan-
tum yields of fluorescence (Φf) remain relatively high, indi-
cating that no photoinduced electron transfer takes place.
Product R1
R2
Conditions Time
Yield (%)
14
14
15
14
15
16
17
18
Ph
Ph
Ph
Ph
Cl
Cl
Ph
Cl
Ph
Cl
CϵCPh
A
B
B
C
C
D
D
E
72 h
15 min
15 min
16 h
22
63
89
72
64
69
56
51
Ph
24 h
CϵCPh
16 h
CϵCPh
24 h
N-piperidine Cl
1 h
[a] A) Conventional Suzuki reaction: PhB(OH)2, Pd(PPh3)4,
Na2CO3, toluene, reflux. B) Microwave Suzuki reaction, toluene,
150 W. C) Stille reaction: Ph4Sn, Pd(PPh3)4, Na2CO3, toluene, re-
flux. D) Sonogashira reaction: phenylacetylene, Pd(PPh3)4, CuI,
THF/iPr2EtN, reflux. E) Hartwig–Buchwald reaction: piperidine,
Pd2dba3, KHMDS, toluene.
Table 3. Spectroscopic data for selected BODIPY dyes in cyclohex-
ane, THF and acetonitrile.
Because microwave irradiation is known to speed up
these reactions, we attempted microwave-enhanced Suzuki
reactions.[7b] Fortunately, we were able to isolate the desired
product 14 (Table 2) in excellent yields after only fifteen
minutes of microwave irradiation at 130 °C. To obtain the
doubly arylated dye 15 it was sufficient to use two equiva-
lents of the boronic acid.
Unlike the Suzuki reactions, the Stille reaction of our
model system with tetraphenyltin proceeded at an accept-
able rate under conventional heating conditions, and either
the monosubstituted 14 or the disubstituted dye 15 were
obtained after reflux in toluene.
The Sonogashira reaction was tested with phenylacetyl-
ene with an amine base in THF at reflux. After a few hours
reaction time at 50 °C, we were able to isolate either the
monosubstituted 16 or the disubstituted product 17 in good
yields. Again, there was good selectivity of the substrate for
monosubstitution over disubstitution. Only small amounts
of the disubstituted product could be observed as the syn-
thesis of monosubstituted dye approached completion.
All attempts to apply the substrate in Heck reactions led
to total decomposition of the chromophore.
Finally, we sought an alternative route to the much
sought-after amine-substituted dyes, which have been im-
possible to prepare by nucleophilic substitution. Hartwig–
Buchwald-type palladium-catalysed aminations have
rapidly become an established route to substituted
amines.[12] Although initial experiments with bases such as
Product Solvent
λabs(max)[a]
λem(max)[b]
ν[c]
Φf
˜
∆
[nm]
[nm]
[cm–1]
5a
5c
5d
11
8
cyclohexane
THF
518
517
514
579
575
568
649
648
645
580
579
575
570
570
560
580
579
570
574
573
565
578
578
568
578
578
570
575
576
568
537
537
532
608
607
602
660
662
657
607
610
603
600
602
593
606
607
603
602
604
603
605
607
601
606
608
599
603
605
600
683
720
658
824
917
994
257
326
283
767
878
808
877
933
994
740
797
960
810
896
1115
772
827
967
799
854
849
808
832
939
0.98
0.66
0.68
0.58
0.57
0.71
0.77
0.47
0.31
0.89
0.52
0.67
0.79
0.74
0.91
0.82
0.57
0.68
0.75
0.63
0.75
0.60
0.62
0.75
0.60
0.54
0.89
0.51
0.43
0.50
CH3CN
cyclohexane
THF
CH3CN
cyclohexane
THF
CH3CN
cyclohexane
THF
CH3CN
cyclohexane
THF
CH3CN
cyclohexane
THF
CH3CN
cyclohexane
THF
CH3CN
cyclohexane
THF
CH3CN
cyclohexane
THF
10
17
14
15
18
CH3CN
cyclohexane
THF
CH3CN
[a] Absorption maximum. [b] Fluorescence emission maximum.
tertiary butoxide or phosphate were unsuccessful, a switch [c] Stokes shift.
5922
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© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 5920–5926

8-(4,6-Dichloropyrimidin-5-yl)-BODIPY
The choice of the pyrrole moiety determines the proper-
Further evidence for this restricted rotation could be
ties of the resulting dye. Through variation of the substitu- found in an X-ray analysis. As shown in Figure 3, the crys-
ents on the pyrrole ring, dyes with absorption and emission tal structure of dye 9 is in line with most previously re-
from green up to the near infrared can be obtained (Fig- ported BODIPY dyes, with the two planar pyrrole subunits
ure 2 and Table 3).
and the boron atom forming a plane in the BODIPY ring
system. The two fluorine atoms are equidistant above and
below the plane of the pyrrole moieties, and the F–B–F
plane is almost perpendicular (89.91°) to the plane of the
BODIPY core. Moreover, the pyrimidine residues and the
BODIPY core are linked to form an approximate orthogo-
nal arrangement, with an angle of 79.69° between the pla-
nes made up by the BODIPY core atoms (B1, N1, C10,
C11, C12, N2) and by the pyrimidine ring (N3, C25, C22,
C23, N4, C24). Steric interactions between the 4Ј-/6Ј-sub-
stituents and the 1- and 7-hydrogen atoms make the rota-
tion energetically strongly disfavoured.
Conclusions
Figure 2. Normalized absorption (dash line) and fluorescence emis-
sion (solid line) spectra of 5a (green), 5c (pink) and 5d (red) in
THF.
We have developed a new and easily accessible BODIPY
scaffold that can be substituted by nucleophilic aromatic
substitution or through transition-metal-catalysed cross-
coupling reactions. The spectral properties of the dyes do
not depend on the introduced substituents, but can be re-
lated directly to the starting 8-(4,6-dichloropyrimidin-5-yl)-
BODIPYs. By this approach, reactive dyes with absorption
and emission spectra throughout the visible spectrum are
available as fluorescent probes and for labelling purposes.
Of particular interest is the fact that the fluorescence
quantum yields (Φf) are high and remain high in solvents of
increasing polarity. This is presumably because of hindered
rotation of the meso-pyrimidyl ring as a consequence of the
4Ј,6Ј-substituents.[13] Rotation of an aryl ring at the 8-posi-
tion has been identified as one of the major pathways of
nonradiative decay of the excited state, and this has been
used to increase Φf through the introduction of bulky aryl
groups or simply by replacing the aryl substituent by hydro-
gen or a small alkyl chain.[5b,14]
Experimental Section
1
General: H and 13C NMR spectra were recorded at room tempera-
ture with a Bruker Avance 300 instrument operating at a frequency
of 300 MHz for 1H and 75 MHz for 13C. In cases of ambiguous
assignments, spectra were recorded with a Bruker Avance 400 or a
Bruker 600. 1H NMR spectra were recorded in CDCl3 and refer-
enced to tetramethylsilane (δ = 0.00 ppm) as an internal standard.
13C NMR spectra were referenced to the CDCl3 (δ = 77.67 ppm)
signal. Mass spectra were recorded with a Hewlett–Packard 5989A
mass spectrometer (EI mode and CI mode). High-resolution mass
data were obtained with a Kratos MS50TC instrument. Melting
points were taken with a Reichert Thermovar and are uncorrected.
Microwave irradiation experiments were carried out with a dedicated
CEM-Discover mono-mode microwave apparatus, operating at a fre-
quency of 2.45 GHz with continuous irradiation power from 0 to
300 W. Absorption spectra were determined with a Varian UV-
Cary 100 spectrophotometer. Fluorescence spectra measurements
were performed with a Hitachi F-4500 spectrofluorimeter. For the
determination of the relative fluorescence quantum yields (Φf), only
dilute solutions with absorbance below 0.1 at the excitation wave-
length (λex) were used. Rhodamine 6G in H2O (λex = 488 nm, Φf =
0.76), rhodamine B in H2O (λex = 540 nm, Φf = 0.41) and cresyl
violet (λex = 560 nm, Φf = 0.55) in methanol were used as fluores-
cence standards. The Φf values reported in this work are the averages
of multiple (generally three or four) fully independent measurements.
The Φf values were determined with non-degassed samples.
Figure 3. ORTEP representation of compound 9 with displacement
CCDC-742655 (for 9) contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via www.ccdc.cam.
ac.uk/data_request/cif.
ellipsoids at the 20% probability level.
A solvent molecule
(CH2Cl2) and H atoms are omitted for clarity. Unit cell parameters:
a 13.2343(7), b 9.6985(5), c 30.3228(17), β 90.321(3), space group
P21/c.
Eur. J. Org. Chem. 2009, 5920–5926
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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5923

W. Dehaen et al.
General Procedure for BODIPY Synthesis. 8-(4,6-Dichloropyrimid- 0.5 mmol, 2.5 equiv.) and K2CO3 (69 mg, 0.5 mmol). The mixture
FULL PAPER
in-5-yl)-3,5-diphenyl-BODIPY (5c): 4,6-Dichloropyrimidine-5-car-
baldehyde (2, 1.77 g, 10 mmol) and 2-phenylpyrrole (3c, 2.86 g,
20 mmol, 2 equiv.) were dissolved in CH2Cl2 (100 mL) under nitro-
gen. A few drops of trifluoroacetic acid were added, and the reac-
tion was followed by TLC. After the disappearance of the starting
was stirred at 100 °C under nitrogen for 4 h. After disappearance
of the starting material, the mixture was poured into diethyl ether
and washed with water (3ϫ100 mL), dried, filtered and concen-
trated to dryness. The crude product was purified by column
chromatography (silica, dichloromethane/petroleum ether 1:1 v/v)
1
material, DDQ (2.27 g, 10 mmol) was added and the mixture was to yield BODIPY 6 (15 mg, 16%) as a red solid; m.p. 235 °C. H
stirred at room temperature for 2 h. The reaction mixture was co-
oled to 0 °C with an ice bath, triethylamine (14 mL, 100 mmol,
10 equiv.) was added, and the solution was stirred for 10 min, after
which boron trifluoride etherate (14 mL, 110 mmol, 11 equiv.) was
added dropwise. The ice bath was removed and the reaction mix-
ture was stirred for 5 d at room temperature. The solution was
taken up in diethyl ether (300 mL), washed with water
(3ϫ200 mL), dried with MgSO4 and filtered, and the solvents were
evaporated to dryness. The crude residue was purified by column
chromatography (silica, dichloromethane/petroleum ether 1:1 v/v)
to yield the BODIPY 5c (3.910 g, 80% total yield) as a purple crys-
NMR (300 MHz): δ = 8.68 (s, 1 H, 1Ј-H), 7.46 (m, 5 H), 6.09 (s, 2
H), 2.61 (s, 6 H), 1.68 (s, 6 H) ppm. 13C NMR (75 MHz): δ = 172,
158.5, 157.9, 141.4, 135.8, 130.4, 130.3, 129.9, 129.7, 126.6, 124.7,
122.1, 15.1, 14.2 ppm. MS (EI): m/z = 468. HRMS: calcd. for
C23H20BClF2N4S 468.1158; found 468.11591.
8-(4-Chloro-6-phenoxypyrimidin-5-yl)-3,5-diphenyl-BODIPY (7):
BODIPY 5c (98 mg, 0.2 mmol) was dissolved in DMF (5 mL), fol-
lowed by the addition of phenol (18.8 mg, 0.2 mmol, 1 equiv.),
K2CO3 (28 mg, 0.2 mmol) and a catalytic amount of 18-crown-6
(2.64 mg, 0.01 mmol, 5%). The mixture was stirred at room tem-
perature until the starting material had disappeared. The mixture
was poured into diethyl ether and washed with water (3ϫ100 mL),
dried, filtered and concentrated to dryness. The crude product was
purified by flash chromatography (silica, dichloromethane/petro-
leum ether 1:1 v/v) to yield BODIPY 7 (107.4 mg, 98%) as a purple
solid; m.p. 130 °C. 1H NMR (300 MHz): δ = 8.70 (s, 1 H, 1Ј-H)
7.91 (d, J = 4.5 Hz, 4 H), 7.43 (m, 8 H), 7.29 (t, J = 7.2 Hz, 1 H),
7.08 (d, J = 7.2 Hz, 2 H), 7.85 (d, J = 3.6 Hz, 2 H), 6.68 (d, J =
3.6 Hz, 2 H) ppm. 13C NMR (75 MHz): δ = 168.5, 161.6, 160.5,
158.7, 152.0, 135.9, 132.3, 131.8, 130.1, 129.9, 129.6, 128.6, 128.5,
126.6, 122.0, 121.6, 114.8 ppm. MS (EI): m/z = 548. HRMS: calcd.
for C31H20BClF2N4O 548.1387; found 548.13968.
1
talline solid; m.p. 102 °C. H NMR (300 MHz): δ = 8.98 (s, 1 H,
1Ј-H), 7.91 (m, 4 H), 7.44 (m, 6 H), 6.67 (s, 4 H) ppm. 13C NMR
(75 MHz): δ = 162.2, 161.1, 158.8, 135.2, 132.1, 131.7, 130.3, 139.7,
128.5, 127.5, 122.4 ppm. MS (EI): m/z = 490. HRMS: calcd. for
C25H15BCl2F2N4 490.07349; found 490.07346.
8-(4,6-Dichloropyrimidin-5-yl)-BODIPY (5a): HCl (37%, 1 mL)
was added to distilled water (250 mL) and the solution was stirred
under nitrogen for 10 min. Pyrrole (2.1 mL, 30 mmol) was added
to the solution, which was stirred until a clear solution was ob-
tained. 4,6-Dichloropyrimidine-5-carbaldehyde (1.77 g, 10 mmol)
was then added in portions over 10 min. After a few min, the clear
solution had become opaque, and a precipitate had begun to form.
The mixture was stirred at room temperature for 6 h, filtered
through a glass filter and thoroughly washed with water. The solid
could be dried under vacuum to yield sufficiently pure dipyrrome-
thane. Further purification could be effected by dissolving the
crude solid in dichloromethane, drying over MgSO4, filtering and
concentrating to dryness. This solid was then stirred in petroleum
ether for 6 h to remove trace impurities. From here on the general
procedure was followed, starting with the oxidation with DDQ.
After oxidation and complexation, the product (745 mg, 22% from
the starting aldehyde) was obtained as a red solid; m.p. 108 °C. 1H
NMR (300 MHz): δ = 8.98 (s, 1 H, 1Ј-H), 8.01 (s, 2 H), 6.72 (s, 2
H), 6.58 (s, 2 H) ppm. 13C NMR (MHz, 75): δ = 159.3, 147.2,
139.9, 120.4 ppm. MS (EI): m/z = 338. HRMS: calcd. for
C13H7BCl2F2N4: 338.01089; found 338.01076.
8-[4,6-Bis(phenoxy)pyrimidin-5-yl]-3,5-diphenyl-BODIPY (8):
BODIPY 5c (98 mg, 0.2 mmol) was dissolved in DMF (5 mL), fol-
lowed by the addition of phenol (37.6 mg, 0.4 mmol, 2 equiv.),
K2CO3 (56 mg, 0.4 mmol) and a catalytic amount of 18-crown-6
(5.2 mg, 0.02 mmol, 5%). The mixture was stirred at 100 °C until
the starting material had disappeared. The mixture was poured into
diethyl ether and washed with water (3ϫ100 mL), dried, filtered
and concentrated to dryness. The crude product was purified by
flash chromatography (silica, dichloromethane/petroleum ether 1:1
v/v) to yield BODIPY 8 (103 mg, 85%) as a purple solid; m.p.
1
218 °C. H NMR (300 MHz): δ = 8.51 (s, 1 H, 1Ј-H), 7.90 (d, J =
5.7 Hz, 4 H), 7.41 (m, 10 H), 7.24 (m, 2 H), 7.11 (d, J = 7.8 Hz, 4
H), 7.04 (d, J = 3.3 Hz, 2 H), 6.69 (d, J = 3 Hz, 2 H) ppm. 13C
NMR (75 MHz): δ = 168.9, 159.8, 158.6, 152.5, 136.7, 132.5, 132.2,
129.8, 129.6, 128.9, 128.4, 126.2, 121.7, 121.6, 100.7 ppm. MS (EI):
m/z = 606. HRMS: calcd. for C37H25BF2N4O2 606.2089; found
606.20569.
8-(4,6-Dichloropyrimidin-5-yl)-1,3,5,7-tetramethyl-BODIPY (5b):
BODIPY 5b (1.18 g, 30% total yield) was obtained by the General
Procedure as a red solid; m.p. 142 °C. 1H NMR (300 MHz): δ =
8.93 (s, 1 H, 1Ј-H), 6.07 (s, 2 H), 2.59 (s, 6 H), 1.54 (s, 6 H) ppm.
13C NMR (75 MHz): δ = 161.6, 158.5, 158.1, 141.1, 129.8, 128.7,
122.3, 15.0, 14.1 ppm. MS (EI): m/z = 394. HRMS: calcd. for
C17H15BCl2F2N4 394.0735 found 394.07362.
8-(4,6-Bis-2-naphthoxypyrimidin-5-yl)-3,5-diphenyl-BODIPY (9):
BODIPY 5c (98 mg, 0.2 mmol) was dissolved in DMF (5 mL), fol-
lowed by the addition of 2-naphthol (57.6 mg, 0.4 mmol, 2 equiv.),
K2CO3 (56 mg, 0.4 mmol) and a catalytic amount of 18-crown-6-
ether (5.2 mg, 0.02 mmol, 5%). The mixture was stirred at 100 °C
until the starting material had disappeared. The mixture was
poured into diethyl ether and washed with water (3 ϫ100 mL),
dried, filtered and concentrated to dryness. The crude product was
purified by flash chromatography (silica, dichloromethane/petro-
leum ether 1:1 v/v) to yield BODIPY 9 (106 mg, 75%) as a purple
Dihydrobenzindole-8-(4,6-dichloropyrimidin-5-yl)-BODIPY
(4d):
BODIPY 4d (1.303 g, 48% total yield for a 5 mmol reaction) was
obtained by the General Procedure as a blue solid; m.p. Ͼ300 °C.
1H NMR (300 MHz): δ = 8.95 (s, 1 H, 1Ј-H), 8.80 (d, J = 7.8 Hz,
2 H), 7.46 (t, J = 7.5 Hz, 2 H), 7.35 (t, J = 7.5 Hz, 2 H), 7.29 (s, 2
H), 6.31 (s, 2 H), 2.94 (t, J = 6.6 Hz, 4 H), 2.70 (t, J = 6.6 Hz, 4
H) ppm. MS (EI): m/z = 542. HRMS: calcd. for C29H19N4BF2Cl2
542.1048; found 542.10487.
1
solid; m.p. 134 °C. H NMR (600 MHz): δ = 8.55 (s, 1 H, 1Ј-H),
7.98 (d, J = 6.6 Hz, 4 H), 7.93 (d, J = 9.0 Hz, 2 H), 7.89 (d, J =
8.4 Hz, 2 H), 7.84 (d, J = 7.8 Hz, 2 H), 7.63 (s, 2 H), 7.49–7.55 (m,
4 H), 7.43–7.49 (m, 6 H), 7.32 (d, J = 9.0 Hz, 2 H), 7.21 (d, J =
4.2 Hz, 2 H), 6.79 (d, J = 4.2 Hz, 2 H) ppm. 13C NMR (75 MHz):
δ = 169.0, 159.9, 158.5, 150.0, 136.7, 133.9, 132.5, 132.1, 131.6,
8-(4-Chloro-6-phenylsulfanylpyrimidin-5-yl)-1,3,5,7-tetramethyl-
BODIPY (6): BODIPY 5b (79 mg, 0.2 mmol) was dissolved in
DMF (5 mL), followed by the addition of thiophenol (103 µL,
5924
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© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 5920–5926

8-(4,6-Dichloropyrimidin-5-yl)-BODIPY
129.9, 129.8, 129.6, 128.9, 128.4, 128.0, 127.7, 126.9, 126.0, 121.6,
121.1, 117.5, 100.8 ppm. MS (ESI): m/z = 707.
added and stirring at 100 °C was continued until the reaction was
complete. The mixture was poured into diethyl ether and washed
with water (3ϫ100 mL), dried, filtered and concentrated to dry-
ness. The crude product was purified by flash chromatography (sil-
ica, dichloromethane/petroleum ether 1:1 v/v) to yield BODIPY 13
(99.5 mg, 80 %) as a purple solid; m.p. 106 °C. 1 H NMR
(400 MHz): δ = 8.69 (s, 1 H, 1Ј-H), 7.91 (d, J = 7.2 Hz, 4 H), 7.46–
7.38 (m, 8 H), 7.24 (t, J = 7.2 Hz, 1 H), 7.07 (d, 2 H), 6.90 (d, J =
7.8 Hz, 2 H), 6.64 (d, J = 4.8 Hz, 2 H), 2.57 (s, 3 H, –SMe) ppm.
13C NMR (200 MHz): δ = 172.2, 165.9, 160.1, 157.9, 152.4, 135.9,
132.4, 129.9, 129.7, 129.69, 129.65, 129.7, 128.4, 126.0, 121.7,
121.6, 111.8, 13.6 ppm. MS (EI): m/z = 560. HRMS: calcd. for
C32H23BF2N4OS 560.16537; found 560.16554.
8-(4-Chloro-6-phenylsulfanylpyrimidin-5-yl)-3,5-diphenyl-BODIPY
(10): BODIPY 5c (98 mg, 0.2 mmol) was dissolved in DMF (5 mL),
followed by the addition of thiophenol (20.5 µL, 0.2 mmol,
1 equiv.) and K2CO3 (28 mg, 0.2 mmol). The mixture was stirred
at room temperature until the starting material had disappeared.
The mixture was poured into diethyl ether and washed with water
(3 ϫ 100 mL), dried, filtered and concentrated to dryness. The
crude product was purified by flash chromatography (silica, dichlo-
romethane/petroleum ether 1:1 v/v) to yield BODIPY 10 (101 mg,
90%) as a purple solid; m.p. 230 °C. 1H NMR (300 MHz): δ = 8.73
(s, 1 H, 1Ј-H), 7.93 (d, J = 3.9 Hz, 4 H), 7.43–7.50 (m, 11 H), 6.80
(s, 2 H), 6.69 (s, 2 H) ppm. 13C NMR (75 MHz): δ = 173.1, 160.8,
159.3, 158.1, 135.7, 135.3, 132.7, 132.2, 130.3, 130.2, 129.7, 129.6,
128.7, 128.5, 127.1, 123.8, 122.2 ppm. MS (EI): m/z = 564. HRMS:
calcd. for C31H20BClF2N4S 564.1158; found 564.11681.
8-(6-Chloro-4-phenylpyrimidin-5-yl)-3,5-diphenyl-BODIPY (14)
Microwave Procedure: BODIPY 5c (98 mg, 0.2 mmol) was dis-
solved in toluene (1 mL) and the resulting solution was purged with
nitrogen. Phenylboronic acid (29 µL, 0.26 mmol, 1.3 equiv.) was
added, followed by tetrakis(triphenylphosphane)palladium (11 mg,
0.02 mmol, 10 mol-%). The mixture was irradiated at 130 °C and
150 W for 15 min, allowed to cool to room temperature and poured
into diethyl ether (150 mL). The organic layer was washed with
water (3ϫ200 mL), dried and filtered, and the solvents were evapo-
rated to dryness. The product was purified by column chromatog-
raphy (silica, CH2Cl2/petroleum ether 1:1, v/v) to yield 14 as a pur-
ple crystalline solid (67 mg, 63 %), together with disubstituted
BODIPY 15 (17 mg, 15%); m.p. of 14: 87 °C
8-[4,6-Bis(phenylsulfanyl)pyrimidin-5-yl]-3,5-diphenyl-BODIPY
(11): BODIPY 5c (98 mg, 0.2 mmol) was dissolved in DMF (5 mL),
followed by the addition of thiophenol (41 µL, 0.4 mmol, 2 equiv.)
and K2CO3 (56 mg, 0.4 mmol). The mixture was stirred at 100 °C
until the starting material had disappeared. The mixture was
poured into diethyl ether and washed with water (3 ϫ100 mL),
dried, filtered and concentrated to dryness. The crude product was
purified by flash chromatography (silica, dichloromethane/petro-
leum ether 1:1 v/v) to yield BODIPY 11 (115 mg, 90%) as a purple
1
solid; m.p. 192 °C. H NMR (600 MHz): δ = 8.59 (s, 1 H, 1Ј-H),
Stille Coupling: BODIPY 5c (98 mg, 0.2 mmol) was dissolved in
toluene (2 mL) and the resulting solution was purged with nitrogen.
Tetraphenyltin (96 mg, 0.22 mmol, 1.1 equiv.) was added, followed
7.95 (d, J = 7.2 Hz, 4 H), 7.49 (d, J = 6.6 Hz, 4 H), 7.45 (m, 6 H),
7.40 (m, 2 H), 6.93 (d, J = 3.6 Hz, 2 H), 6.71 (d, J = 3.6 Hz, 2
H) ppm. 13C NMR (150 MHz): δ = 168.9, 160.5, 157.7, 135.6, by tetrakis(triphenylphosphane)palladium (11 mg, 0.01 mmol,
135.5, 132.4, 130.0, 129.8, 129.7, 129.4, 128.9, 128.4, 128.0, 122.0,
121.8 ppm. MS (EI): m/z = 638. HRMS: calcd. for C37H25BF2N4S2
638.1582; found 638.15739.
5 mol-%) and Na2CO3 (2 mL, 1  solution in H2O). The mixture
was heated at reflux for 16 h, allowed to cool to room temperature,
and poured into diethyl ether (150 mL). The organic layer was
washed with water (3ϫ200 mL), dried and filtered, and the sol-
vents were evaporated to dryness. The product was purified by col-
umn chromatography (silica, CH2Cl2/petroleum ether 1:1, v/v) to
yield 14 as a purple crystalline solid (76 mg, 72%).
1H NMR (300 MHz): δ = 9.22 (s, 1 H, 1Ј-H), 7.87 (d, J = 4.5 Hz,
4 H), 7.73 (d, J = 6.6 Hz, 2 H), 7.33–7.45 (m, 9 H), 6.67 (d, J =
3.3 Hz, 2 H), 6.59 (s, 2 H) ppm. 13C NMR (75 MHz): δ = 167.0,
162.2, 160.2, 158.9, 136.2, 136.1, 134.8, 132.1, 131.1, 130.1, 129.7,
129.0, 128.9, 128.4, 125.6, 122.1 ppm. MS (EI): m/z = 532. HRMS:
calcd. for C31H20BClF2N4 532.14376; found 532.14381.
8-(4-Phenoxy-6-phenylsulfanylpyrimidin-5-yl)-3,5-diphenyl-BODIPY
(12): BODIPY 5c (98 mg, 0.2 mmol) was dissolved in DMF (5 mL),
followed by the addition of phenol (18.8 mg, 0.2 mmol, 1 equiv.),
K2CO3 (56 mg, 0.4 mmol) and a catalytic amount of 18-crown-6
(2.64 mg, 0.01 mmol, 5%). The mixture was stirred at 100 °C until
TLC analysis indicated complete disappearance of the starting ma-
terial. Thiophenol (20.5 µL, 0.2 mmol, 1 equiv.) was then added
and stirring at 100 °C was continued until the reaction was com-
plete. The mixture was poured into diethyl ether and washed with
water (3ϫ100 mL), dried, filtered and concentrated to dryness. The
crude product was purified by flash chromatography (silica, dichlo-
romethane/petroleum ether 1:1 v/v) to yield BODIPY 12 (99.5 mg,
8-(4,6-Diphenylpyrimidin-5-yl)-3,5-diphenyl-BODIPY (15):
BODIPY 5c (98 mg, 0.2 mmol) was dissolved in DMF (1 mL) and
the resulting solution was purged with nitrogen. Phenylboronic acid
(29 µL, 0.26 mmol, 1.3 equiv.) was added, followed by tetrakis(tri-
phenylphosphane)palladium (11 mg, 0.02 mmol, 10 mol-%) and
CuI (3.8 mg, 0.02 mmol, 10 mol-%). The mixture was irradiated at
130 °C and 150 W for 15 min, allowed to cool to room temperature
and poured into diethyl ether (150 mL). The organic layer was
washed with water (3ϫ200 mL), dried and filtered, and the sol-
vents were evaporated to dryness. The product was purified by col-
umn chromatography (silica, CH2Cl2/petroleum ether 1:1, v/v) to
yield 15 as a purple crystalline solid (102 mg, 89%); m.p. 140 °C.
1H NMR (300 MHz): δ = 9.51 (s, 1 H, 1Ј-H), 7.80 (s, 4 H), 7.64 (s,
2 H), 7.36 (m, 12 H), 6.62 (s, 2 H), 6.43 (s, 2 H) ppm. 13C NMR
(75 MHz): δ = 166.4, 159.1, 159.0, 137.8, 137.5, 136.8, 132.1, 130.2,
129.9, 129.6, 129.4, 128.7, 128.3, 124.4, 121.7 ppm. MS (EI): m/z
= 574. HRMS: calcd. for C37H25BF2N4 574.2140; found 574.21.
1
80%) 12 as a purple solid; m.p. 112 °C. H NMR (600 MHz): δ =
8.37 (s, 1 H, 1Ј-H), 7.97 (d, J = 7.2 Hz, 4 H), 7.46 (d, J = 7.2 Hz,
2 H), 7.09 (t, J = 7.2 Hz, 4 H), 7.05 (m, 2 H), 7.04 (t, J = 3.0 Hz,
2 H), 7.02 (t, J = 7.2 Hz, 3 H), 6.95 (d, J = 7.8 Hz, 2 H), 6.88 (t,
J = 7.2 Hz, 1 H), 6.67 (d, J = 4.8 Hz, 2 H), 6.38 (d, J = 4.2 Hz, 2
H) ppm. 13C NMR (150 MHz): δ = 171.7, 166.4, 160.2, 128.3,
152.3, 136.1, 135.6, 133.2, 132.4, 130.0, 129.9, 129.8, 129.7, 129.4,
128.9, 128.4, 128.0, 126.1, 121.8, 121.7, 111.7 ppm. MS (EI): m/z
= 622. HRMS: calcd. for C37H25BF2N4SO 622.1810; found
622.17992.
8-(4-Methylsulfanyl-6-phenoxypyrimidin-5-yl)-3,5-diphenyl-BODIPY
(13): BODIPY 5c (98 mg, 0.2 mmol) was dissolved in DMF (5 mL),
followed by the addition of phenol (18.8 mg, 0.2 mmol, 1 equiv.),
K2CO3 (28 mg, 0.2 mmol) and a catalytic amount of 18-crown-6
(2.64 mg, 0.01 mmol, 5%). The mixture was stirred at 100 °C until
TLC analysis indicated complete disappearance of the starting ma-
terial. Sodium thiomethoxide (15 mg, 0.2 mmol, 1 equiv.) was then
8-(4-Chloro-6-phenylethynylpyrimidin-5-yl)-3,5-diphenyl-BODIPY
(16): BODIPY 5c (98 mg, 0.2 mmol) was dissolved in THF (2 mL)
Eur. J. Org. Chem. 2009, 5920–5926
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5925

W. Dehaen et al.
FULL PAPER
and iPr2NEt (1 mL) and the resulting solution was purged with
nitrogen. Phenylacetylene (29 µL, 0.26 mmol, 1.3 equiv.) was
added, followed by tetrakis(triphenylphosphane)palladium (11 mg,
0.01 mmol, 5 mol-%) and CuI (1.9 mg, 0.01 mmol, 5 mol-%). The
mixture was heated at reflux for 3 h and allowed to cool to room
temperature, after which the solvent was stripped. The product was
purified by column chromatography (silica, CH2Cl2/petroleum
ether 1:1, v/v) to yield 16 as a purple crystalline solid (76 mg, 69%);
m.p. 193 °C. 1H NMR (300 MHz): δ = 9.12 (s, 1 H, 1Ј-H), 7.90 (d,
J = 4.2 Hz, 4 H), 7.43 (s, 6 H), 7.34 (m, 3 H), 7.26 (m, 2 H), 6.76
(s, 2 H), 6.65 (s, 2 H) ppm. 13C NMR (75 MHz): δ = 160.7, 160.6,
159.1, 152.6, 135.7, 133.7, 133.0, 132.2, 130.9, 130.1, 129.6, 129.4,
129.1, 128.7, 128.5, 122.1, 120.2, 102.2 (CϵC), 85.5 (CϵC) ppm.
MS (EI): m/z = 556. HRMS: calcd. for C33H20BClF2N4 556.1438;
found 556.14355.
Scientific Research Fund for Introducing Talented Persons to
Lanzhou University.
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8-[4,6-Bis(phenylethynyl)pyrimidin-5-yl]-3,5-diphenyl-BODIPY (17):
BODIPY 5c (98 mg, 0.2 mmol) was dissolved in THF (2 mL) and
iPr2NEt (1 mL), and the resulting solution was purged with nitro-
gen. Phenylacetylene (29 µL, 0.26 mmol, 1.3 equiv.) was added,
followed by tetrakis(triphenylphosphane)palladium (11 mg,
0.02 mmol, 10 mol-%) and CuI (3.8 mg, 0.02 mmol, 10 mol-%).
The mixture was heated at reflux for 3 h and allowed to cool to
room temperature, after which the solvent was stripped. The prod-
uct was purified by column chromatography (silica, CH2Cl2/petro-
leum ether 1:1, v/v) to yield 17 as a purple crystalline solid (69 mg,
1
56%); m.p. 218 °C. H NMR (300 MHz): δ = 9.31 (s, 1 H, 1Ј-H),
7.92 (d, J = 4.5 Hz, 4 H), 7.44 (m, 6 H), 7.33 (m, 6 H), 7.27 (m, 4
H), 6.89 (d, J = 3.6 Hz, 2 H), 6.64 (d, J = 2.7 Hz, 2 H) ppm. 13C
NMR (75 MHz): δ = 160.2, 159.4, 150.9, 136.2, 135.7, 132.9, 132.4,
131.7, 130.6, 130.0, 129.8, 129.6, 128.7, 128.5, 121.9, 120.6, 101.1
(CϵC), 85.9 (CϵC) ppm. MS (EI): m/z = 622. HRMS: calcd. for
C41H25BF2N4 622.2140; found 622.21376.
8-(4-Chloro-6-piperidinopyrimidin-5-yl)-3,5-diphenyl-BODIPY (18):
BODIPY 5c (98 mg, 0.2 mmol) was dissolved in toluene (2 mL)
and the resulting solution was purged with nitrogen. Piperidine
(13 µL, 0.26 mmol, 1.3 equiv.) was added, followed by trisdibenzyli-
dene-acetone-dipalladium (9 mg, 0.02 mmol, 10 mol-%), BINAP
(24.9 mg, 0.04 mmol, 20 mol-%) and KHMDS (30 mg, 0.03 mmol,
1.5 equiv.). The mixture was flushed with nitrogen and heated at
110 °C in a closed vessel for 1 h. The vessel was allowed to cool to
room temperature, after which the solvent was stripped. The prod-
uct was purified by column chromatography (silica, CH2Cl2/petro-
leum ether 1:1, v/v) to yield 18 as a purple crystalline solid (54 mg,
1
51%); m.p. 200 °C. H NMR (400 MHz): δ = 8.48 (s, 1 H, 1Ј-H),
7.89 (d, J = 4.5 Hz, 4 H), 7.43 (m, 6 H), 6.88 (d, J = 4.28 Hz, 2
H), 6.64 (d, J = 4.28 Hz, 2 H), 3.66 (t, J = 5.28 Hz, 4 H), 1.57 (m,
2 H), 1.41 (m, 4 H) ppm. 13C NMR (100 MHz): δ = 161.9, 160.7,
159.9, 127.6, 1237.4, 135.9, 132.3, 129.9, 129.7, 129.6, 129.6, 129.2,
128.4, 121.6, 109.0, 48.7, 25.8, 24.5 ppm. MS (EI): m/z = 622.
HRMS: calcd. for C30H25BClF2N5 539.1859; found 539.18545.
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Acknowledgments
The Instituut voor de aanmoediging van innovatie door Weten-
schap en Technologie in Vlaanderen (IWT) is acknowledged for
a fellowship to V. L. We thank the Fonds voor Wetenschappelijk
Onderzoek (FWO), the Ministerie voor Wetenschapsbeleid and the
K. U. Leuven for continuing financial support. W. Q. thanks the
Received: June 30, 2009
Published Online: October 8, 2009
5926
www.eurjoc.org
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 5920–5926