Radical C-H Alkylation of BODIPY Dyes Using Potassium Trifluoroborates or Boronic Acids

Article abstract of DOI:10.1002/chem.201500938

A one-step synthetic procedure for the radical C H alkylation of BODIPY dyes has been developed. This new reaction generates alkyl radicals through the oxidation of boronic acids or potassium trifluoroborates and allows the synthesis of mono-, di-, tri-,

Full text of DOI:10.1002/chem.201500938

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
DOI: 10.1002/chem.201500938
Full Paper
&
Dyes
Radical CÀH Alkylation of BODIPY Dyes Using Potassium
Trifluoroborates or Boronic Acids**
Bram Verbelen,[a] Lucas Cunha Dias Rezende,[a, b] Stijn Boodts,[a] Jeroen Jacobs,[a]
Luc Van Meervelt,[a] Johan Hofkens,[a] and Wim Dehaen*[a]
Abstract: A one-step synthetic procedure for the radical CÀ in a good to excellent yield for a broad range of organobor-
H alkylation of BODIPY dyes has been developed. This new
reaction generates alkyl radicals through the oxidation of
boronic acids or potassium trifluoroborates and allows the
synthesis of mono-, di-, tri-, and tetraalkylated fluorophores
on compounds. Using this protocol, multiple bulky alkyl
groups can be introduced onto the BODIPY core thus creat-
ing solid-state emissive BODIPY dyes.
BODIPY dyes, such as halogenated compounds[8] or derivatives
containing a thioether as a pseudohalogen.[9] Although these
two methodologies are well documented, they tend to suffer
from the use of unstable intermediates and/or the need for
a long synthetic route.
Introduction
Among the known fluorophores, BODIPY dyes (4,4-difluoro-4-
bora-3a,4a-diaza-s-indacenes, also known as boron dipyrrome-
thenes or as boron dipyrrins)[1] have become an increasingly
valuable class of compounds over the last two decades. Their
growing success is mainly attributed to the many excellent
characteristics they possess, such as a bright fluorescence in
the visible spectral range and a good robustness towards light
and chemicals.[2] The growing importance of these boron com-
plexes is evident in the numerous applications being reported
for these dyes. These applications include their use as chemo-
sensors,[3] potential photosensitizers in photodynamic thera-
py,[4] laser dyes,[5] and photoactive materials in organic photo-
voltaic devices.[5,6]
These two disadvantages can be avoided by introducing
functional groups more efficiently onto the BODIPY core, for
example, by using CÀH functionalization reactions,[10–12] allow-
ing the synthesis of new fluorophores in a single atom eco-
nomical step. In the last few years, a handful of examples of
such direct derivation reactions for boron dipyrrins have been
described, namely, nucleophilic substitution of hydrogen[13]
and palladium-catalyzed CÀH arylation[14] at the 3,5-positions,
and palladium-catalyzed CÀH alkenylation[15] and CÀH aryla-
tion[16] and iridium-catalyzed borylation[17] at the 2,6-positions.
Most of these developed direct functionalization reactions are
based on CÀH activation and require rather forcing conditions
to overcome the inertness of a CÀH bond. Unfortunately, an
appreciable amount of decomposition of the BODIPY substrate
may occur under harsh reaction conditions, reducing the ob-
tained yield, complicating purification, and limiting the sub-
strate scope.
The rich functionalization chemistry of these fluorophores is
undoubtedly another major reason for the attractiveness of
these boron-dipyrromethene (BODIPY) dyes. It allows a practi-
cally unlimited structural modification and hence leads to so-
phisticated dyes with fine-tuned chemical, optical, and (photo)-
physical properties. The typical derivation strategy mostly
starts from suitably functionalized pyrroles[7] or uses reactive
In contrast, because of the high reactivity of radical species
as compared with the reagents used in CÀH activation reac-
tions, radical CÀH functionalization can take place under mild
conditions. In this way, the problems associated with CÀH acti-
vation of boron dipyrromethenes can be avoided. Recently,
our group had demonstrated this by developing a radical CÀH
arylation at the 3,5-positions, based on the ferrocene-catalyzed
reduction of aryldiazonium salts.[18] This proved to be a versa-
tile, general, high-yielding method for the synthesis of brightly
fluorescent 3,5-diarylated and 3-monoarylated BODIPY dyes.
Most reactions to functionalize BODIPY fluorophores de-
scribed so far are arylation, alkenylation, or alkynylation reac-
tions. Up to this point, only three alkylation reactions have
been described. The first two alkylation reactions are both nu-
cleophilic substitutions of hydrogen using carbon nucleo-
[a] B. Verbelen, L. Cunha Dias Rezende, S. Boodts, J. Jacobs,
Prof. L. Van Meervelt, Prof. J. Hofkens, Prof. W. Dehaen
Department of Chemistry, KU Leuven
Celestijnenlaan 200f–bus 02404, 3001 Leuven (Belgium)
E-mail: Wim.Dehaen@chem.kuleuven.be
[b] L. Cunha Dias Rezende
Faculdade de CiÞncias FarmacÞuticas
de Ribeir¼o Preto, Universidade de S¼o Paulo
Av. Do CafØ s/n, Ribeir¼o Preto, SP, 14040-903 (Brazil)
[**] BODIPY=boron-dipyrromethene
Supporting information for this article (containing experimental procedures,
characterization data (1H and 13C NMR spectra, absorption and emission
spectra of all new compounds), a table with the solid state fluorescence
properties of the powders of the cyclohexylated dyes 4, 5 and 6a and the
crystallographic data of tetracyclohexyl-BODIPY 6a) is available on the
WWW under http://dx.doi.org/10.1002/chem.201500938.
Chem. Eur. J. 2015, 21, 12667 – 12675
12667
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
Full Paper
philes.[13] Although these methods use relatively mild condi-
tions, the scope is rather limited because only enolates can
react in this type of transformation. The last reported alkylation
reaction uses a Negishi reaction between organozinc reagents
and halogenated boron dipyrromethenes to introduce simple
primary alkyl groups.[19] In the case of secondary alkyl groups,
isomerization occurred to form a mixture of compounds. Fur-
ther disadvantages of this alkylation method are the need for
dry reaction conditions and the use of halogenated boron di-
pyrrins, which require extra steps and unstable halogenated
pyrrole intermediates.
Table 1. Optimization of the radical CÀH alkylation of 8-(2,6-dichloro-
phenyl)-BODIPY 1a using potassium cyclohexyltrifluoroborate 2a.[a,b]
Entry Oxidant
Solvent
T
[8C]
t
Yield
[%][c]
1
[Mn(OAc)3]·2H2O
1,2-dichloroethane 50
45 h
23 h
22.5 h 35
23 h
22 h
19 h
4 d
4 d
4 d
19 h
24.5 h 46
52
77
2[d]
3
[Mn(OAc)3]·2H2O
[Mn(OAc)3]·2H2O
[Mn(OAc)3]·2H2O
[Mn(OAc)3]·2H2O
[Mn(OAc)3]·2H2O
K2Cr2O7
DMF
50
50
50
50
50
50
50
50
50
50
RT
80
A more general and straightforward alkylation of BODIPY
dyes could be possible with a radical CÀH alkylation reac-
tion.[11] Possible radical precursors for this transformation are
boronic acids as well as potassium trifluoroborates. Both these
compounds are known to decompose into radicals through
a single-electron transfer in the presence of an oxidant.[12,20]
Hence, oxidation of alkylboronic acids or potassium alkyltri-
fluoroborates can form alkyl radicals, and this could prove to
be an interesting method to alkylate boron dipyrromethenes.
Herein, we report our investigation on the use of stoichiomet-
ric alkylboronic acids and potassium alkyltrifluoroborates as
radical precursors in a direct CÀH alkylation of readily available
meso-substituted BODIPY dyes 1.
acetone
DMSO
MeOH
toluene
DMF
4
5
6
7
8
9
10
11[f]
12
13
30
40
18
28
CuCl2
DMF
trace
trace
[Ce(NH4)4(SO4)4]·2H2O DMF
p-chloranil
[Mn(OAc)3]·2H2O
[Mn(OAc)3]·2H2O
[Mn(OAc)3]·2H2O
[e]
DMF
DMF
DMF
DMF
–
46 h
4.5 h
36
68[g]
[a] Experimental conditions: 8-(2,6-dichlorophenyl)-BODIPY 1a (0.1 mmol),
potassium cyclohexyltrifluoroborate 2a (1 equiv), oxidant (2.5 equiv), sol-
vent (1 mL), stirring for the indicated time at the indicated temperature.
[b] Ar is 2,6-dichlorophenyl. [c] Yields of the isolated product. [d] Highest
yielding conditions. [e] No reaction occurred. [f] One equivalent of oxi-
dant was used. [g] Dicyclohexylated side-product 4 (21%) was also isolat-
ed.
Results and Discussion
Optimization of the reaction
good selectivity of mono- over difunctionalization of this radi-
cal CÀH reaction.
A well-known example of a single-electron oxidant in the field
of radical chemistry is manganese(III) acetate.[21] Hence, this
salt is often used for the oxidation of boronic acids and potas-
sium trifluoroborates to generate radicals. This oxidant was
consequently used for a trial reaction between 8-(2,6-dichloro-
phenyl)-BODIPY 1a and cyclohexylboronic acid 2 f. Cyclohexy-
lation was chosen due to the combination of commercial avail-
ability of the starting compound and ease of purification of
the desired product. This reaction was carried out in 1,2-di-
chloroethane at 508C, but unfortunately only a trace amount
of product was formed after two days. Perhaps oxidation of
the boronic acid was inefficient under these conditions. On the
other hand, the more electron-rich potassium cyclohexyltri-
fluoroborate 2a (Table 1, entry 1) resulted in a more efficient
formation of cyclohexyl radicals under the same reaction con-
ditions. Hence, the desired cyclohexyl-BODIPY 3a was, to our
delight, formed in a good yield of 52% after reacting for 45 h
at 508C.
To further improve the yield, the alkylation reaction was
tested in various solvents (Table 1, entries 1–6), using different
oxidants (Table 1, entries 7–10) and using different amounts of
oxidant (Table 1, entry 11). The reaction in DMF using
2.5 equivalents of manganese(III) acetate resulted in the high-
est yield, providing the desired 3-cyclohexyl-BODIPY 3a in an
excellent yield of 77% after 23 h. Using a slight excess of tri-
fluoroborate resulted in an identical yield. The effect of tem-
perature was also investigated. At room temperature, instead
of 508C, the cyclohexyl-product 3a was isolated in a lower
yield after a longer reaction time (Table 1, entry 12). A substan-
tial amount of starting material was still present in the crude
mixture after 46 h. On the other hand, the reaction was com-
pleted in a few hours at 808C (Table 1, entry 13). However, dia-
lkylation became significant at this higher temperature, provid-
ing 3,5-dicyclohexyl-BODIPY 4 in 21% yield as a side product,
which reduced the monoalkylation yield.
Characterization of the alkylated product 3a of this reaction
revealed that the cyclohexyl radical reacted exclusively at the
3-position of the BODIPY core. Such a high regioselectivity for
radical reactions on boron dipyrromethenes has been demon-
strated before with our previously published radical CÀH aryla-
tion.[17] This was explained using the strongly polarizing effect
the BF2 group has on the dipyrromethene core. Furthermore,
only a trace amount of the 3,5-dialkylated product 4 was
formed during this radical alkylation, demonstrating the very
Scope of the reaction
With the optimal conditions in hand, we investigated the
scope of this radical CÀH transformation by executing this re-
action with different BODIPY substrates and a range of trifluor-
oborates (Table 2). Different meso-substituted boron dipyrro-
methenes 1a–e could be cyclohexylated, providing the alkylat-
ed product 3a–e in a good to excellent yield (Table 2, en-
Chem. Eur. J. 2015, 21, 12667 – 12675
www.chemeurj.org
12668
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
Full Paper
scribed before.[19b] This can be attributed to the more
difficult oxidation of primary organoboron com-
pounds as compared with secondary and tertiary de-
rivatives. Hence, if an electron-donating group is
present to increase the electron density of the a-
carbon, such a limited formation of the alkyl radical
through oxidation should not be a problem. Indeed,
the use of potassium benzyloxymethyltrifluoroborate
2j resulted in the formation of the expected 3-(ben-
zyloxymethyl)-BODIPY dye 3j (Table 2, entry 10). To
our regret, this alkylated fluorophore proved to be
unstable under the used reaction conditions and was
lost during the reaction. The scope of this radical
transformation is not limited to simple unfunctional-
ized alkyl groups: trifluoroborates bearing an ester
group (2k and 2l) reacted to form ester functional-
ized BODIPY dyes (3k and 3l) in good yield (Table 2,
entries 11 and 12). These experiments illustrate the
generality of this radical CÀH reaction. When we
compared the results to other reported alkylation re-
actions of boron dipyrromethenes[13,18] it becomes
apparent that this radical alkylation possess a signifi-
cantly broader scope. Thus, a great variety of alkylat-
ed BODIPY fluorophores can be synthesized using
a simple protocol without the need for reactive
boron dipyrrin derivatives.
Table 2. Scope of the radical CÀH functionalization of BODIPY fluorophores using po-
tassium trifluoroborates and boronic acids.[a]
Entry
Compound
Ar
R
t
[h]
Yield
[%][b]
1
a
b
c
2,6-dichlorophenyl
phenyl
23
77
60
50
58
44
67
60
2
19
3
mesityl
19.5
18.5
18.5
20
4
d
e
f
4-nitrophenyl
methylthio
5
6[c]
7
2,6-dichlorophenyl
2,6-dichlorophenyl
2,6-dichlorophenyl
g
h
19
8
19
76
9
i
j
2,6-dichlorophenyl
2,6-dichlorophenyl
20
18
trace[d]
[e]
10
–
11
k
2,6-dichlorophenyl
20
51
12
l
2,6-dichlorophenyl
2,6-dichlorophenyl
2,6-dichlorophenyl
2,6-dichlorophenyl
18.5
22.5
18
57
42
42
34
Potassium alkyltrifluoroborates are not the only
known type of trifluoroborates: Aryl, alkenyl and al-
kynyl derivatives can also be prepared. Subsequently,
we investigated the reactivity of these substrates
under the optimized conditions. Using potassium ar-
yltrifluoroborates 2m–n, we synthesized the corre-
sponding 3-aryl-BODIPYs 3m–n in moderate yield
(Table 2, entries 13 and 14). These yields are not com-
petitive with those obtained by using our previously
reported CÀH arylation methodology,[18] although this
reaction could still prove to be a useful alternative.
Also, a reaction was observed in the case of potassi-
um trans-b-styryltrifluoroborate 2p. Unfortunately,
because of the nature of the radical reaction, isomeri-
zation of the double bond takes place. Accordingly,
a mixture of cis- and trans-3-styryl-BODIPY was isolat-
ed in 39% yield, with a cis/trans ratio of 16:84. After
a crystallization of this mixture, pure trans-3-styryl-
13
m
n
o
14
15[c]
20
16
17
p
q
2,6-dichlorophenyl
2,6-dichlorophenyl
19
19
20
[f]
–
[a] Experimental condition: BODIPY 1 (0.1 mmol), potassium alkyltrifluoroborate 2
(1 equiv), [Mn(OAc)3]·2H2O (2.5 equiv), DMF (1 mL), stirring for the indicated time at
508C. [b] Yield of the isolated product. [c] Corresponding boronic acid was used in-
stead of the potassium trifluoroborate. [d] Formation of alkylated product observed
by using mass spectrometry (EI mode). [e] Product was formed, as detected by using
mass spectrometry (EI mode), but was not stable under the reaction condition and
decomposed. [f] No reaction occurred.
tries 1–5). The product formed from meso-(methylthio)-BODIPY
1e is interesting, because its thioether substituent provides an
opportunity to further functionalize this alkylated dye.[9] Not
only cyclohexylation is possible, as both tertiary and acyclic
secondary alkyltrifluoroborates were reactive under these con-
ditions, producing 3-tert-butyl-BODIPY 3g (Table 2, entry 7)
and 3-sec-butyl-BODIPY 3h (Table 2, entry 8) in a straightfor-
ward fashion in similar yields. Unfortunately, a primary organo-
boron compound, such as potassium octyltrifluoroborate 2i
(Table 2, entry 9), did not give the expected product under
these conditions. Only a trace amount of the desired 3-octyl-
boron dipyrrin 3i was detected. Such a low reactivity of pri-
mary trifluoroborates in these type of reactions has been de-
BODIPY 3p was obtained in a yield of 20% (Table 2, entry 14).
Thus, this is not a very effective reaction compared with the
direct alkenylation procedure previously reported by our
group.[13b] Lastly, the reactivity of potassium(phenylethynyl)tri-
fluoroborate 2q was tested, but regrettably no CÀH alkynyla-
tion reaction took place (Table 2, entry 17).
Because of the greater availability of boronic acids, we
wanted to revisit their application under our optimized condi-
tions. Hence, the use of boronic acids as the radical precursor
for the functionalization of boron dipyrrins was tested once
more. To our delight, the use of cyclohexylboronic acid 2 f
under these conditions resulted in the formation of the desired
3-cyclohexyl-BODIPY 3 f in a good yield (Table 2, entry 6). How-
Chem. Eur. J. 2015, 21, 12667 – 12675
www.chemeurj.org
12669
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
Full Paper
ever, the resulting yield was 10% lower than when potassium
cyclohexyltrifluoroborate 2a was used. This lower yield is pre-
sumably due to the less-efficient oxidation of a boronic acid as
compared with a more electron-rich trifluoroborate, as de-
scribed above. Similarly, using 4-methoxyphenylboronic acid
2o the corresponding 4-methoxyphenyl-BODIPY 3o could be
synthesized in an 8% lower yield than the trifluoroborate ex-
ample (Table 2, entry 14 and 15). Lastly, the pinacol ester of cy-
clohexylboronic acid was investigated as a radical source
under our optimized condition, unfortunately after 42 h only
a trace amount of the 3-cyclohexyl-BODIPY 3 f was formed.
When the dialkylation reaction was complete at 808C
(Table 3, entry 4), trace amounts of tricyclohexyl-BODIPY 5 and
tetracyclohexyl-BODIPY 6a were formed as well as the main di-
cyclohexyl product 4. At 908C, an even higher amount of tri-
and tetracyclohexylated dyes were formed. However, because
of the increased decomposition and side-product formation in
this case, the complete purification of these products was not
possible. Still, by using a higher amount of potassium cyclo-
hexyltrifluoroborate 2a, the reaction at 808C could be modi-
fied to allow further alkylation of the boron dipyrromethene
core (Scheme 1). Thus, treatment of 8-(2,6-dichlorophenyl)-
Extension to di-, tri-, and tetraalkylation
When studying the effect of temperature on the radical mono-
alkylation reaction (see above), we observed that dialkylation
became significant at a higher temperature. Consequently, the
reaction was no longer selective for monoalkylation at this
temperature. Accordingly, we investigated if this radical reac-
tion could be modified to allow dialkylation using 2 equiva-
lents of potassium cyclohexyltrifluoroborate 2a to effectively
synthesize 3,5-dicyclohexyl-BODIPY 4. To this end, the CÀH di-
alkylation reaction was executed at higher temperatures
(Table 3). As the temperature increases, the reaction time de-
Table 3. Optimization of the radical CÀH dialkylation of 8-(2,6-dichloro-
phenyl)-BODIPY 1a using potassium cyclohexyltrifluoroborate 2a.[a,b]
Scheme 1. Tri- and tetraalkylation of meso-substituted BODIPY dyes 1 using
an excess of potassium cyclohexyltrifluoroborate 2a at higher temperatures.
BODIPY 1a with 3 equivalents of the organoboron compound
2a resulted in the formation of 1,3,5-tricyclohexyl-BODIPY 5 in
a yield of 57%. On the other hand, using 4.5 equivalents of the
same trifluoroborate 2a gave 53% of 1,3,5,7-tetracyclohexyl-
BODIPY 6a. Similarly, 8-phenyl-BODIPY 1b could be tetraalky-
lated in a comparable yield. It should be mentioned that the
tetracyclohexylation of 8-phenyl-BODIPY 1b was significantly
faster than the reaction of the more sterically hindered 8-(2,6-
dichlorophenyl) derivative 1a, with the reaction being com-
pleted in 3.5 h for the 8-phenyl dye 1b and in 19.5 h for the di-
chlorophenyl dye 1a. Hence, this radical transformation allows
the synthesis of boron dipyrrin dyes with multiple sec-alkyl
substituents, such as 1,3,5,7-tetracyclohexyl-BODIPYs 6. The
synthesis for these compounds has not been described previ-
ously. Characterization of the formed 1,3,5,7-tetracyclohexyl-
BODIPY 6a using X-ray diffraction (see below) showed that the
cyclohexyl radical reacted exclusively at the 1,7-positions once
the 3,5-positions were occupied. To investigate if the 2,6- or 8-
positions are at all reactive towards radicals, the less sterically
hindered 1,3,5,7-tetramethyl-BODIPY was subjected to the de-
veloped radical alkylation condition with potassium cyclohexyl-
trifluoroborate 2a. Despite that the 2,6- and 8-positions are
unsubstituted in this molecule, no reaction was observed and
the starting material was recovered. This once more illustrates
the high selectivity of these radical reactions.
Entry
T
[8C]
t
Dialkylation
yield [%][c]
1
2
3
4[d]
5
50
60
70
80
90
45 h
44 h
21 h
2 h
23
64
86
92
14
45 min
[a] Experimental condition: 8-(2,6-dichlorophenyl)-BODIPY 1a (0.1 mmol),
potassium cyclohexyltrifluoroborate 2a (2 equiv), [Mn(OAc)3]·2H2O
(5 equiv), DMF (1 mL), stirring for the indicated time at the indicated tem-
perature. [b] Ar is 2,6-dichlorophenyl. [c] Yields of the isolated products.
[d] Highest yielding conditions.
creases and the yield of the dicyclohexyl product 4 increases.
The reaction is completed after 2 h at 808C, providing the 3,5-
dicyclohexyl fluorophore 4 in an excellent yield of 92%
(Table 3, entry 4). However, at even higher temperatures, de-
composition of the starting compound 1a became problemat-
ic, causing an in situ excess of trifluoroborate 2a and hence
a significant formation of tricyclohexyl-BODIPY 5. This, com-
bined with a rather difficult separation due to the extra side
products being formed in this case, resulted in a drastically
lower yield when the reaction was complete at 908C (Table 3,
entry 5).
Chem. Eur. J. 2015, 21, 12667 – 12675
www.chemeurj.org
12670
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim