Direct palladium-catalysed C-H arylation of BODIPY dyes at the 3- and 3,5-positions

Article abstract of DOI:10.1039/c2cc34549h

A new one-step synthetic method towards 3- and 3,5-arylated BODIPY dyes via palladium-catalysed C-H arylation has been developed and its scope has been investigated.

Full text of DOI:10.1039/c2cc34549h

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Direct palladium-catalysed C–H arylation of BODIPY dyes at the 3- and
3,5-positions†
Bram Verbelen, Volker Leen, Lina Wang, Noël Boens, Wim Dehaen*
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000x
starting material was recovered.
A new one-step synthetic method towards 3- and 3,5-arylated
BODIPY dyes via palladium-catalysed C–H arylation has
been developed and its scope has been investigated.
50
Characterisation of the formed product 2a showed that
bromobenzene had reacted at the electrophilic 3ꢀposition.
Therefore, the most likely mechanism for this C–H activation
Boron complexes of dipyrromethenes, or 4,4ꢀdifluoroꢀ4ꢀboraꢀ
10 3a,4aꢀdiazaꢀsꢀindacenes (BODIPY), are valuable fluorophores
because of their many excellent characteristics, such as bright 55 dimethylpropanoate) is known to accelerate C–H
is
a
concerted metallationꢀdeprotonation involving the
carbonate as an intramolecular base.12 Since pivalate (i.e. 2,2ꢀ
fluorescence, robustness towards light and chemicals, and
excitation/emission wavelengths in the visible spectral range.1
Therefore, they have numerous applications, including the use
15 as chemosensors.2 Since the spectroscopic and photophysical
functionalisation proceeding via this mechanism,13 addition of
a substoichiometric amount of pivalic acid (PivOH, i.e., 2,2ꢀ
dimethylpropanoic acid) to the reaction mixture was tested.
As expected, this sped up the C–H arylation. The estimated in
properties of these boron complexes can be simply tuned by 60 situ yield determined via NMR spectroscopy increased from
substituting the BODIPY nucleus, much investigation is
ongoing on the synthesis and functionalisation of these
fascinating molecules. Most strategies to derivatise the core of
20 boron dipyrromethenes either start from functionalised
4% after 4 days without pivalic acid (Table S1, entry 2, ESI)
to 17% with this additive (Table S1, entry 4).
However, further improvement was needed (Table S1) and
hence, other reaction conditions were tried. By changing the
pyrroles,3 use halogenated BODIPYs4 or utilise the 65 ligand with more electron rich or bidentate ligands (entries 4ꢀ
LiebeskindꢀSrogl reaction.5
A more efficient method to derivatise molecules is the use
of transitionꢀmetalꢀcatalysed C–H functionalisation reactions.6
25 During the last decade, these atom economical reactions have
7) and by altering the palladium source (entries 8 and 9), it
was found that palladium(II) acetate and
tricyclohexylphosphine were the best catalyst and ligand
combination. Furthermore, different bases were tested (entries
become an increasingly attractive alternative to traditional 70 10ꢀ13), including more soluble bases and a pivalate salt, but
crossꢀcoupling reactions. Thanks to the advancements in this
area, heteroaromatic systems now can be easily functionalised
via, for instance, direct arylations.7
all were inferior to K2CO3. Varying the solvent (entries 14ꢀ18)
showed that apolar solvents like toluene and oꢀxylene gave the
best results. Of different arylhalides tested (entries 19 and 20),
bromoarenes were the best reagents.
30
In the case of BODIPY, only a few examples of direct
functionalisations
are
known,
namely
nucleophilic
75
Under these conditions the arylation was tried with
different bromoarene reagents (Table 1). The yields were only
fair, largely because diarylation is an important side reaction
and because separating monoꢀ 2 and diarylꢀBODIPYs 3 is
cumbersome, leading to product loss due to mixed column
substitution of hydrogen at the 3,5ꢀpositions,8 and direct
alkenylation9 and direct borylation10 at the 2,6ꢀpositions. Also,
previously our group successfully used an intramolecular
35 direct arylation to synthesize ringꢀfused BODIPY dyes.11
Such transitionꢀmetalꢀcatalysed C–H functionalisations are 80 chromatography fractions. Electron rich (entries 2 and 4),
interesting alternative strategies to substitute the BODIPY
core and to create fluorophores with redꢀshifted electronic
spectra. Therefore, we set out to investigate the feasibility of
40 direct intermolecular palladiumꢀcatalysed C–H arylation on
heteroaromatic (entry 4), sterically hindered (entry 5) and
ringꢀfused bromoarenes (entry 6) can be used in this arylation
reaction. However, reaction with 4ꢀbromoꢀN,Nꢀdimethylꢀ
aniline (entry 3) resulted only in decomposition of the starting
via 85 BODIPY. Interestingly, reaction with sterically hindered 2ꢀ
bromoꢀ1,3,5ꢀtrimethylbenzene (entry 5) did not produce a
readily available mesoꢀsubstituted BODIPY dyes
1
reaction with arylhalides.
The condition previously optimized by our group for the
diarylated product and only monoarylation, albeit in a lower
yield, occured. Disappointingly, the reaction of electron poor
bromoarenes (entries 7 and 8) proceeded very slowly under
intramolecular direct βꢀarylation,11 was used to test the
45 intermolecular C–H arylation of boron dipyrromethenes 1
with bromobenzene. To our delight, the desired phenylꢀ 90 the current reaction conditions. After 2 days there was not
BODIPY 2a was indeed formed after 48 h, although in a low
yield. Due to the slow speed of the reaction the majority of the
enough product formed to allow a complete characterisation,
although TLC analysis showed product formation.
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Table 1 Scope of the direct C–H arylation of mesoꢀsubstituted
BODIPY with different bromoarenes
Yield (%)b
Reaction
time
Entry Compound
Ara
2
3
1
2
3
4
5
a
b
c
d
e
f
Phenylc,d
4ꢀAnisyld
24 h
43 h
44
42
ꢀk
17
10
ꢀk
4ꢀ(Dimethylamino)ꢀphenyld 48 h
3ꢀThienyld
Mesityld
27 h
43 h
24 h
48 h
48 h
28 h
46 h
4 days
4 days
3 h
55
35
20l
ꢀm
10
0
Scheme 1 Synthesis of an asymmetric BODIPY and a BODIPY dimer
6
1ꢀNaphthylc,d
4ꢀCyanophenyld
3ꢀNitrophenyld
Phenylc,e
16
using the developed C–H arylation method
7
8
9
g
h
i
ꢀm
ꢀm
ꢀm
45 (entry 9) and pꢀnitrophenyl (entry 10) derivatives, were
reactive in this type of arylation albeit with slightly lower
yields.
31l
28
13
ꢀn
39
26
28
32
18
43
39
40
ꢀn
10
11
12
13
14
15
j
k
l
m
n
o
Phenylc,f
Phenyld,g
Phenylc,d,h
Phenyld,i
Lastly, to illustrate the possibilities of this novel reaction,
an asymmetric dye 4 and a BODIPY dimer 5 were prepared
50 using the developed direct arylation. The asymmetric system 4
was prepared by performing two successive C–H arylations,
the first with bromobenzene (entry 1), the second with 3ꢀ
bromothiophene (Scheme 1). The second arylation proceeded
in a much higher yield (62%) than the previous reactions,
55 because the diarylation side reaction was not an issue with the
3ꢀsubstituted dye 2a. Because this phenylꢀsubstituted dye 2a
reacted with such a good yield, it was chosen as the substrate
3ꢀThienyld,i
Phenyld,i,j
3 h
3,5 h
46
a
Experimental condition: 5 mol% Pd(OAc)2, 10 mol% HPCy3BF4, 30
mol% PivOH, 3 equivalents K2CO3, 1.1 equivalents bromoarene, toluene
5
at 110 °C. b All yields are isolated yields. c oꢀxylene is used as solvent at
110 °C. d R is 2,6ꢀdichlorophenyl. e R is phenyl. f R is pꢀnitrophenyl. g 2.2
h
equivalents of bromobenzene were used.
10 equivalents of
bromobenzene were used. i Microwave irradiation, irradiated at 110 °C.
j
5 equivalents of bromobenzene were used. k Only decomposition occurs. l
m
10 Low yield because of difficult purification. Very slow reaction, only
starting material retrieved. n No pure compound could be obtained.
for
a double C–H arylation with 1,4ꢀdibromobenzene,
resulting in the BODIPY dimer 5 in 23% yield (Scheme 1).
60 Indeed, the unsymmetrical dye 4 or dimer 5 would be difficult
to prepare from substituted pyrrole building blocks.
The variety of the aromatic groups at the 3,5,8ꢀpositions of the
BODIPY nucleus of 1–5 provides a set of dyes with absorption
and fluorescence emission spectra covering a broad range of the
65 visible spectrum (Figure 1). Here we summarize the key results
of the spectroscopic investigation. Full details will be described
elsewhere.
The spectra display the characteristic narrow absorption and
fluorescence emission bands of classic difluoroboron
70 dipyrromethenes. As a function of the solvent, the spectral
maxima are located within a very narrow wavelength range and
are slightly redꢀshifted with increasing solvent polarizability,
which is the crucial parameter affecting the wavelength position
of the maxima. The broadest spectral bands are found for the 1ꢀ
75 naphthyl substituted derivatives 2f and 3f, and bisꢀBODIPY 5.
The Stokes shifts are generally quite small with exceptions for 2f,
3f and 5. The extended πꢀconjugation in the 3,5ꢀdiaryl products 3
always leads to bathochromically shifted absorption and emission
spectra compared to those of the 3ꢀsubstituted analogues 2.
80 Derivative 2e (with 3ꢀmesityl substituent) has blueꢀshifted spectra
compared to 2a (with 3ꢀphenyl group), reflecting the diminished
π ꢀconjugation in 2e and indicating that steric hindrance (between
2ꢀH of BODIPY and mesityl oꢀMe) rotates the mesityl group out
of the BODIPY plane. The nature of the mesoꢀsubstituent has
85 only a small effect on the spectral positions. The majority of the
dyes have high fluorescence quantum yields (Ф > 0.85), except
for the analogues with mesoꢀphenyl (2i and 3i) and mesoꢀpꢀ
nitrophenyl (2j and 3j) substituents. Free rotation of the 8ꢀaryl
Next, it was tested whether diarylꢀBODIPY 3 could be
selectively synthesized by using two equivalents of
bromobenzene over a longer reaction time. This resulted in an
15 acceptable yield of the desired diaryl product 3k (entry 11).
Unfortunately, the monoarylꢀBODIPY 2k was still present,
which made the purification rather difficult. The use of a
significant excess of bromobenzene (entry 12) was not
helpful.
20
Since these C–H arylations require rather long reaction
times, the use of microwave irradiation to accelerate the
reaction was investigated. Both the monoarylation (entries 13
and 14) and the diarylation (entry 15) protocol became
significantly faster under this type of heating. In the case of
25 monoarylation with bromobenzene (entry 13), a similar yield
as with conventional heating (entry 1) was obtained for the
mono product, although a larger amount of diarylation
occurred thus resulting in a higher conversion. However,
applying this microwave protocol to arylate with 3ꢀ
30 bromothiophene (entry 14), the highest yielding reagent with
conventional heating, resulted in
a large amount of
decomposition and thus a lower yield. In the case of
diarylation (entry 15), a similar yield was obtained as with
conventional heating (entries 11 and 12) but in a significantly
35 shorter amount of time. Attempts to push this reaction further
by irradiating at 150 °C for
decomposition.
3 h resulted only in
To demonstrate the generality of this C–H arylation
protocol, this reaction was performed with different mesoꢀ
40 substituted BODIPYs. This showed that not only the mesoꢀ
2,6ꢀdichlorophenyl derivative (entry 1), but also the phenyl
2
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(e) L. Li, B. Nguyen and K. Burgess, Bioorg. Med. Chem. Lett.,
2008, 18, 3112; (f) E. Fron, E. CoutiñoꢀGonzalez, L. Pandey, M.
Sliwa, M. Van der Auweraer, F.C. De Schryver, J. Thomas, Z.
Dong, V. Leen, M. Smet, W. Dehaen and T. Vosch, New J. Chem.,
2009, 33, 1490; (g) V. Leen, E. Braeken, K. Luckermans, C.
Jackers, M. Van der Auweraer, N. Boens and W. Dehaen, Chem.
Commun., 2009, 4515; (h) Y. Cakmak and E.U. Akkaya, Org. Lett.,
2009, 11, 85; (i) V. Leen, D. Miscoria, S. Yin, A. Filarowski, J.M.
Ngongo, M. Van der Auweraer, N. Boens and W. Dehaen, J. Org.
Chem., 2011, 76, 8168; (j) G. Ulrich, A. Haefele, P. Retailleau and
R. Ziessel, J. Org. Chem., 2012, 77, 5036.
5
6
(a) E. PeñaꢀCabrera, A. AguilarꢀAguilar, M. GonzálezꢀDomínguez,
E. Lager, R. ZamudioꢀVázquez, J. GodoyꢀVargas and F.
VillanuevaꢀGarcía, Org. Lett., 2007, 9, 3985; (b) J. Han, O.
Gonzalez, A. AguilarꢀAguilar, E. PeñaꢀCabrera and K. Burgess,
Org. Biomol. Chem., 2009, 7, 34; (c) I.J. Arroyo, R. Hu, B.Z. Tang,
F.I. López and E. PeñaꢀCabrera, Tetrahedron, 2011, 67, 7244.
(a) X. Chen, K.M. Engle, D.ꢀH. Wang and J.ꢀQ. Yu, Angew. Chem.,
Int. Ed., 2009, 48, 5094; (b) L. Ackermann, Chem. Rev., 2011, 111,
1315.
Fig. 1 Normalized, visible absorption spectra and corresponding
normalized fluorescence emission spectra of a selection of mesoꢀ(2,6ꢀ
dichlorophenyl) substituted BODIPY dyes (1, 2d, 2f, 3d, 4) in THF.
7
(a) L. Ackermann, R. Vicente and A.R. Kapdi, Angew. Chem., Int.
Ed., 2009, 48, 9792; (b) L. Ackermann, R. Vicente, M. Miura, T.
Satoh, P. de Mendoza and A.M. Echavarren, in Modern Arylation
Methods, ed. L. Ackermann, WileyꢀVCH, Weinheim, 1st edn.,
2009, ch. 9ꢀ11, pp. 311ꢀ400.
(a) V. Leen, V.Z. Gonzalvo, W.M. Deborggraeve, N. Boens and W.
Dehaen, Chem.Commun., 2010, 46, 4908; (b) V. Leen, M. Van der
Auweraer, N. Boens and W. Dehaen, Org. Lett., 2011, 13, 1470.
C. Thivierge, R. Bandichhor and K. Burgess, Org. Lett., 2007, 9,
2135.
5
group in the latter dyes enhances nonradiative deactivation of the
S1 excited state, yielding low Ф values, whereas restriction of
rotation of the 8ꢀ(2,6ꢀdichlorophenyl) group leads to high Ф
values.14 The presence of a nitro function in 2j and 3j contributes
extra to fluorescence quenching. Since the number of known bisꢀ
10 BODIPY dyes is rather limited, extra information on such
derivatives is valuable. Therefore, Table S2 (ESI) lists some
relevant spectroscopic data on compound 5.
8
9
10 J. Chen, M. Mizumura, H. Shinokubo and A. Osuka, Chem. Eur. J.,
2009, 15, 5942.
11 V. Leen, W. Qin, W. Yang, J. Cui, C. Xu, X. Tang, W. Liu, K.
Robeyns, L. Van Meervelt, D. Beljonne, R. Lazzaroni, C. Tonnelé,
N. Boens and W. Dehaen, Chem. Asian J., 2010, 5, 2016.
12 S.I. Gorelsky, D. Lapointe and K. Fagnou, J. Org. Chem., 2012, 77,
658.
In conclusion, a general method for the preparation of
brightly fluorescent 3,5ꢀarylated BODIPY dyes with redꢀ
15 shifted electronic spectra utilizing C–H functionalisation has
been developed, thus avoiding the tedious synthesis of
13 (a) B. Liégault, D. Lapointe, L. Caron, A. Vlassova and K. Fagnou,
J. Org. Chem., 2009, 74, 1826; (b) H.ꢀY. Sun, S.I. Gorelsky, D.R.
Stuart, L.C. Campeau and K. Fagnou, J. Org. Chem., 2010, 75,
8180; (c) D. Lapointe and K. Fagnou, Chem. Lett., 2010, 39, 1118.
14 H. L. Kee, C. Kirmaier, L. Yu, P. Thamyongkit, W. J. Youngblood,
M. E. Calder, L. Ramos, B. C. Noll, D. F. Bocian, W. R. Scheidt, R.
R. Birge, J. S. Lindsey and D. Holten, J. Phys. Chem. B, 2005, 109,
20433.
substituted
pyrrole
building
blocks
and
unstable
intermediates. We are currently working towards conditions to
improve the selectivity of monoarylation over diarylation and
20 to expand the scope of this reaction.
Notes and references
Department of Chemistry, KU Leuven, Celestijnenlaan 200f – bus 02404,
3001 Leuven, Belgium. Fax: +32 16 327990; Tel: +32 16 327439;
E-mail: wim.dehaen@chem.kuleuven.be
25 † Electronic Supplementary Information (ESI) available: Experimental
procedures, synthesis optimisation study, characterisation data and UV–
vis spectroscopic data. See DOI: 10.1039/b000000x/
1
(a) A. Loudet and K. Burgess, Chem. Rev., 2007, 107, 4891; (b) G.
Ulrich, R. Ziessel and A. Harriman, Angew. Chem., Int. Ed., 2008,
47, 1184; (c) A. Treibs and F.ꢀH. Kreuzer, Justus Liebigs Ann.
Chem., 1968, 718, 208.
2
3
N. Boens, V. Leen and W. Dehaen, Chem. Soc. Rev., 2012, 41,
1130; and references cited therein.
(a) F. Monsma, A. Barton, H. Kang, D. Brassard, R. Haughland and
D. Sibley, J. Neurochem., 1989, 52, 1641; (b) A. Burghart, H. Kim,
M.B. Welch, L.H. Thoresen, J. Reibenspies and K. Burgess, J. Org.
Chem., 1999, 64, 7813; (c) A. Coskun, M.D. Yilmaz and E.U.
Akkaya, Org. Lett., 2007, 9, 607; (d) K. Umezawa, A. Matsui, Y.
Nakamura, D. Citterio and K. Suzuki, Chem. Eur. J., 2009, 15,
1096.
4
(a) M. Baruah, W. Qin, N. Basarić, W.M. De Borggraeve and N.
Boens, J. Org. Chem. 2005, 70, 4152; (b) M. Baruah, W. Qin,
R.A.L. Vallée, D. Beljonne, T. Rohand, W. Dehaen and N. Boens,
Org. Lett. 2005, 7, 4377; (c) T. Rohand, M. Baruah, W. Qin, N.
Boens and W. Dehaen, Chem. Commun., 2006, 266; (d) T. Rohand,
W. Qin, N. Boens and W. Dehaen, Eur. J. Org. Chem., 2006, 4658;
This journal is © The Royal Society of Chemistry [year]
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