Rapid and selective electrophilic trifluoromethylation of the 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (BODIPY) scaffold

Article abstract of DOI:10.1002/ejoc.201402874

This report deals with the rapid functionalization of the 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (BODIPY) scaffold by means of electrophilic trifluoromethylation. Subjecting dye 2 to the disclosed protocol led to the successful isolation of 3-trifluoromethylated derivative 9. Subsequent comparison of structural and electronic properties allowed for the characterization of changes imparted by the CF₃ group. A diminution in the quantum yield [Φ _F(2)_MeOH = 0.15, Φ _F(9)_THF = 0.024] was accompanied by a larger Stokes shift [ΔS(2)_MeOH = 12 nm, ΔS(9)_THF = 54 nm], whereas the molar extinction coefficient at the global absorbance maximum remained largely unaffected [ε(2)_MeOH = 40 × 10³ M ^-1 cm^-1, ε(9)_THF = 30 × 10³ M ^-1 cm^-1]. A protocol for the rapid trifluoromethylation of the BODIPY scaffold, based on a mixture of 3,3-dimethyl-1-(trifluoromethyl)-3H-1λ3,2-benziodaoxole and iPrSH, is presented. The electronic and structural changes imparted by the CF₃ moiety are studied by NMR and UV/Vis spectroscopy and X-ray crystallography.

Full text of DOI:10.1002/ejoc.201402874

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201402874
Rapid and Selective Electrophilic Trifluoromethylation of the 4,4-Difluoro-4-
bora-3a,4a-diaza-s-indacene (BODIPY) Scaffold
[a]
[a][‡]
ˇ [a]
Nico Santschi,*[a,b] Ján Cvengros, Coraline Matthey, Elisabeth Otth,
and
Antonio Togni[a]
Keywords: Synthetic methods / Trifluoromethylation / Fluorine / Fluorescence / Dyes/Pigments / Regioselectivity
This report deals with the rapid functionalization of the 4,4-
difluoro-4-bora-3a,4a-diaza-s-indacene (BODIPY) scaffold
by means of electrophilic trifluoromethylation. Subjecting
dye 2 to the disclosed protocol led to the successful isolation
of 3-trifluoromethylated derivative 9. Subsequent compari-
son of structural and electronic properties allowed for the
characterization of changes imparted by the CF3 group. A
diminution in the quantum yield [ΦF(2)MeOH = 0.15, ΦF(9)THF
0.024] was accompanied by larger Stokes shift
[ΔS(2)MeOH = 12 nm, ΔS(9)THF = 54 nm], whereas the molar
=
a
extinction coefficient at the global absorbance maximum
remained largely unaffected [ε(2)MeOH = 40ϫ103
M ,
–1 cm–1
ε(9)THF = 30ϫ103
M
–1 cm–1].
vent-independent fluorescence quantum yields, large molec-
ular extinction coefficients up to 320000 m–1 cm–1, and, typi-
cally, small Stokes shifts (ca. 10 nm).[3] Consequently, these
intriguing structures have found numerous applications. For
instance, they have been used as chemodosimeters for fluor-
ide-ion detection, and their implementation as on-site sin-
glet oxygen generators applicable in photodynamic therapy
was considered.[4] Furthermore, 18F analogs have been cre-
ated for hybrid optical and positron emission tomography
imaging.[5] Generally, these molecules are accessed by rely-
ing on the condensation of prefunctionalized pyrrole start-
ing materials and suitable aldehydes or carboxylic acid
derivatives rather than subjecting an abundant BODIPY
framework to further derivatization strategies.[6] In this re-
gard, one of the most remarkable developments in recent
years was the introduction of Biellmann’s BODIPY deriva-
tive 2, the meso position of which could be further derivat-
ized by means of Liebeskind–Srogl cross-coupling method-
ology.[7] Moreover, Tang and Peña-Cabrera showcased in
2009 for the first time that a palladium-catalyzed reduction
of the thioether functionality granted access to parent
BODIPY 3,[8] which paralleled the more conventional syn-
theses reported at the same time by Tram et al. and Schmitt
et al.[9] Other rapid diversification strategies are based on
nucleophilic aromatic substitution reactions (SNAr) per-
formed on 3-chloro or 3,5-dichloro precursors.[10] In this
context, also the incorporation of the strongly electron-
withdrawing CF3 group (σpara = 0.54)[11] at the meso carbon
atom was considered, which thereby rendered 3,5-dichloro
scaffold 4 more susceptible to exchange reactions.[12] Ac-
cordingly, functionalization of Avidin with 4 was achieved
under mild, aqueous conditions. Additionally, in these bio-
conjugates the CF3 group was envisaged as a small
19F NMR reporter probe. Most recently, congener 5 was
Introduction
Since the initial preparation of the 4,4-difluoro-4-bora-
3a,4a-diaza-s-indacene (BODIPY) core in 1968 by Treibs
and Kreuzer in the form of structure 1 (Figure 1),[1] the
central motif has emerged as a privileged framework for
designing stable fluorescent dyes.[2] Usually, this develop-
ment is attributed to several factors including largely sol-
Figure 1. The first reported BODIPY dye 1, Biellmann’s derivative
2, and trifluoromethylated congeners 4–6.
[a] Department of Chemistry and Applied Biosciences,
Swiss Federal Institute of Technology, ETH Zürich,
Vladimir-Prelog-Weg 2, 8093 Zürich, Switzerland
http://www.tognigroup.ethz.ch
[b] Organisch-Chemisches Institut, Westfälische
Wilhelms-Universität Münster,
Corrensstrasse 40, 48149 Münster, Germany
E-mail: santschi@uni-muenster.de
[‡] Crystallographic work
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201402874.
Eur. J. Org. Chem. 2014, 6371–6375
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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N. Santschi, J. Cvengrosˇ, C. Matthey, E. Otth, A. Togni
SHORT COMMUNICATION
found to display aggregation-induced emission enhance- CF3 and BF2 moieties and, hence, suggest functionalization
ment contrasting the photophysical behavior of methylated of the 3,5-positions. In addition, the chemical shifts were in
derivative 6.[13]
good agreement with values reported for 2-(trifluoro-
Correspondingly, the incorporation of the CF3 group methyl)-1H-pyrrole (–59.2 ppm).[24] Unsurprisingly, the use
into the BODIPY platform can lead to highly desirable of an excess amount of 2 (2–4 equiv.) led to increased selec-
modifications of inherent reactivity and electronic proper- tivity for the presumably monofunctionalized product.
ties and, hence, demands further attention. However, to the Hence, a mixture of 2 (4 equiv.) and 7 (1 equiv.) in CH2Cl2
best of our knowledge the feasibility of the late-stage tri- at ambient temperature was treated with iPrSH (2 equiv.) in
fluoromethylation of the pyrrole subunits of the BODIPY CH2Cl2 (Scheme 1). Subsequent chromatographic purifica-
scaffold has not yet been addressed.[14] Herein, a synthetic tion over silica gel afforded the newly formed product as a
protocol providing access to the desired motif is reported, red crystalline solid in 37% yield. Generally, these reactions
the salient features of which include operational simplicity went to completion over the course of minutes. In stark
and very short reaction times. Furthermore, structural and contrast, the MTO-based protocol performed by employing
electronic changes resulting from the trifluoromethylation reagent 8 only led to degradation of the starting materials.
are discussed.
TBAI catalysis with 7 furnished the same product; however,
chromatographic purification was more tedious, and there-
fore, the whole procedure was less practical.
Results and Discussion
Since the advent of 3,3-dimethyl-1-(trifluoromethyl)-3H-
1λ3,2-benziodaoxole (7) and 1-(trifluoromethyl)-3H-1λ3,2-
benziodaoxol-3-one (8),[15] a plethora of methods for gener-
·
ating an electrophilic trifluoromethyl radical (CF3 ) through
reduction of these structures have sprouted (Figure 2). No-
tably, modification of a broad variety of electron-rich and
electron-deficient aromatic systems has been reported by
utilizing 8 in conjunction with catalytic amounts of
MeReO3 (MTO) at elevated temperatures.[16] Additionally,
the desired reactive intermediate was also observed in the
presence of photoredox catalysts,[17] copper sources[18] and
deprotonated oximes.[19] More recent examples have em-
ployed tetrabutylammonium iodide (TBAI) as a an initia-
tor.[20] In accordance, thiols, with typical reduction poten-
tials ranging from 0.8 to 1 V,[21] were also envisioned to pro-
Scheme 1. Radical trifluoromethylation of BODIPY 2.
1H NMR spectroscopy revealed the presence of five aro-
matic signals between δ = 6.50 and 7.77 ppm attributable
to two individual sets of coupling partners by correlation
spectroscopy (COSY). The 19F NMR spectrum revealed a
triplet at δ = –60.3 ppm (JFF = 11.4 Hz, 3 F) and a pseu-
doquartet of quartets at δ = –145.1 ppm (1JBF = 27.9 Hz,
JFF = 11.7 Hz, 2 F), and accordingly, 11B NMR spec-
troscopy furnished a triplet at δ = 0.0 ppm (1JBF = 27.8 Hz).
Finally, HRMS (ESI) showed [M + H]+ at m/z = 307.0498,
which is in line with the calculated mass of m/z = 307.0496
for protonated 9. Gratifyingly, also single crystals suitable
for solid-state structure analysis were obtained by vapor dif-
fusion of pentane into a saturated solution of 9 in acetone
at 4 °C. The most important bond lengths for dye 9 and
parent compound 2 are given in Table 1. An ORTEP repre-
sentation of 9 is found in Figure 3.
A bond length comparison between the substituted (α)
and the unfunctionalized pyrrole subunit (β) in 9 uncovers
small differences, ΔXXЈ, on average of 0.019 Å. In symmet-
ric parent compound 2, the same consideration reveals less
distinct variations (0.005 Å), which are mostly attributable
to measurement uncertainties and packing effects. There-
fore, if ΔXXЈ Ն 0.01 Å, then this difference ΔXXЈ is pre-
sumably a direct consequence of pyrrole functionalization.
Judged by this criterion, bonds A/AЈ–F/FЈ in the pyrrole α
and β subunits of compound 9 are dissimilar and are clearly
·
vide CF3 from 7 and 8.[22] Specifically, upon treatment of
7 with a prototypical thiol RSH at ambient temperature the
occurrence of the corresponding disulfide byproduct (RS)2
alongside the desired RSCF3 was noted, which thereby
hinted towards the involvement of radical species.[23] As a
logical consequence, the functionalization of suitable nu-
cleophiles, namely, a BODIPY derivative, by interception
of these electrophilic radicals was conceived. Therefore, in
consideration of the previously outlined versatility of deriv-
ative 2, the applicability of the rationale to effect the tri-
fluoromethylation of this structure was tested.
Figure 2. Electrophilic trifluoromethylating agents.
To our delight, treatment of a mixture of 2 and 7 with distinguishable as a result of the introduction of the CF3
iPrSH furnished new BODIPY dyes, as suggested by moiety. In addition, the C8–SMe bond lengths indicate a
19F NMR spectroscopy. Particularly, the occurrence of trip- shortening of 0.019 Å upon modifying dye 2 (Table 1, en-
let-like signals around δ = –62.0 ppm with coupling con- try H). Thus, the substitution of hydrogen for the trifluoro-
stants J = 11–13 Hz was noted. These patterns most likely methyl group furthered electron donation through lone
arise from through-space 19F–19F coupling between the pairs of electrons on the sulfur atom, which thereby lends
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Eur. J. Org. Chem. 2014, 6371–6375

Rapid and Selective Electrophilic Trifluoromethylation of BODIPY
Table 1. Comparison of X-ray-derived bond lengths for compounds
9 and 2.
Figure 4. BODIPY resonance structures.
Bond[a]
9 [Å]
ΔXXЈ [Å][b]
2 [Å][b][7]
ΔXXЈ [Å]
A
AЈ
B
BЈ
C
CЈ
D
DЈ
E
EЈ
F
FЈ
G
GЈ
H
1.3603(16)
1.3422(17)
1.3835(18)
1.4013(19)
1.3937(19)
1.3680(20)
1.4022(18)
1.4237(18)
1.3852(16)
1.3998(16)
1.4370(17)
1.4024(18)
1.5439(18)
1.5427(17)
1.7112(13)
+0.0181
1.346
1.341
1.378
1.386
1.374
1.369
1.405
1.409
1.392
1.387
1.408
1.405
1.542
1.538
1.730
+0.005
served in the 13C NMR spectrum, in that the carbon atoms
belonging to the α subunit are shielded between 0.2 and
19.5 ppm relative to the corresponding carbon atoms be-
longing to the β-pyrrole unit (see the Experimental Sec-
tion). In addition, for the pyrrole nitrogen Nα and Nβ atoms
the 15N NMR chemical shifts of δ = 181.3 and 201.9 ppm,
–0.0178
+0.0257
–0.0215
–0.0146
+0.0346
+0.0012
n/a
–0.008
+0.005
–0.004
+0.005
+0.003
+0.004
n/a
1
respectively, could be derived by means of H/15N HSQC
spectroscopy, which substantiates the electronic similarity
of the heteroatoms found in the crystal structure (the 15N
chemical shift range is roughly 800 ppm). Furthermore,
1
stronger H/13C HMBC contacts between the methyl thio-
ether and the proton at C7 are indicative of a solution-phase
orientation that is comparable to the one found in the solid
state. Lastly, a very pronounced effect of the CF3 group on
[a] For 9, ΔXXЈ is the difference in bond length between the func-
tionalized α-pyrrole subunit and the unfunctionalized β-pyrrole
subunit, e.g., A–AЈ. For 2, it is the difference between the left and the electronic structure of the dye is observed as well, as
the right subunit. [b] Asymmetric unit contains two independent
molecules.
evidenced by the UV/Vis spectrum of 9 obtained in THF
(Figure 5). The spectrum exhibits two well-separated max-
ima at λmax 387 (ε = 14.9Ϯ0.2ϫ103 m–1 cm–1) and 470 nm
(ε = 30.1Ϯ0.2ϫ103 m–1 cm–1), which give rise to a hypso-
chromic shift of Δλmax = 21 nm relative to the λmax of 2
[λmax(THF) = 491 nm; λmax(MeOH) = 527 nm, εMeOH
=
40ϫ103 m–1 cm–1]. Subsequent irradiation of a 4.7 μm THF
solution of 9 at 470 nm resulted in fluorescence emission
around λem = 524 nm with an associated Stokes shift of ΔS
= 54 nm, which is roughly four times larger than the value
reported for 2 in MeOH (ΔS = 12 nm).
Figure 3. ORTEP representation of 9. Hydrogen atoms are omitted
for clarity, and thermal ellipsoids are set to 50% probability. Devia-
tion from perfect planarity is indicated by an angle of 9.56° be-
tween the two pyrrole α and β subunits.
increased weight to a resonance structure bearing a formal
positive charge at the chalcogen atom (Figure 4). Markedly,
however, the BF2 unit is complexed symmetrically in both
9 and 2 with comparable B–N bonds G/GЈ of 1.544/1.543 Å
and 1.542/1.538 Å, respectively. Therefore, similar electron
densities at the α- and β-nitrogen atoms were expected, a
fact that was further substantiated by the 15N NMR chemi-
cal shifts (see below).
Figure 5. UV/Vis absorption spectrum (solid) and fluorescence
spectra for λex = 470 nm (dashed) and λex = 387 nm (dot-dashed)
of dye 9 in THF.
Finally, in compound 2, the deviation from perfect plan-
In addition, fluorescence quantum yields of ΦF(9)THF =
arity of the ligand, as defined by the angle between planes 0.0244 and 0.0237 against the standards 9,10-diphenyl-
parallel to the pyrrole moieties, is 6.11°, whereas in 9 a anthracene and perylene, respectively, were obtained, which
slightly larger angle of 9.56° is calculated. This deviation is contrast the reported value of ΦF(2)MeOH = 0.15 of the par-
likely to cause a quantum yield for 9 that is slightly dimin- ent structure. Indeed, this result further corroborates the
ished relative to that of 2. Electronic differentiation as a electron-deficient nature of 9, as quenching of the excited
direct consequence of the trifluoromethylation is also ob- state by intramolecular charge transfer from the meso
Eur. J. Org. Chem. 2014, 6371–6375
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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6373

N. Santschi, J. Cvengrosˇ, C. Matthey, E. Otth, A. Togni
SHORT COMMUNICATION
heteroatom is expected to become more favorable.[25] Fi-
nally, in agreement with Kasha’s rule,[26] if the excitation
wavelength was set to 387 nm, the main emission was still
centered around 524 nm, which corresponds to a pseudo-
Stokes shift of ΔS = 137 nm. In light of recent endeavors
to access dyes with large Stokes shifts for applications as
molecular imaging probes, the findings delineated above are
topical and are currently of high interest. Studies directed
towards further conjugation of product 9 by means of
cross-coupling methodology are ongoing and will be re-
ported in due time.
Supporting Information (see footnote on the first page of this arti-
cle): Synthesis of compound 2, copies of the NMR spectra and
quantum yield determination for compound 9.
Acknowledgments
The ETH Zürich is acknowledged for financial support. R. Zscho-
che and P. Gaweł are acknowledged for assistance with fluorescence
measurements and quantum yield determinations, respectively.
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Conclusions
In summary, the direct trifluoromethylation of the
BODIPY scaffold was achieved through interception of re-
active intermediates generated by treatment of reagent 7
with a thiol. The salient features of the protocol include
no requirement for dried solvents, an inert atmosphere, or
rigorous temperature control, and generally, short reaction
times (Ͻ10 min) are observed. Application of the protocol
to dye 2 resulted in novel derivative 9, which features a
Stokes shift that is approximately four times larger than
that of 2 and a fluorescence quantum yield of ΦF(9)THF
0.024.
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Experimental Section
4,4-Difluoro-8-(thiomethyl)-3-(trifluoromethyl)-4-bora-3a,4a-diaza-
s-indacene (9): 3,3-Dimethyl-1-(trifluoromethyl)-3H-1λ3,2-benz-
iodaoxole (7; 88 mg, 0.27 mmol, 1 equiv.) was added to a solution
of BODIPY-SMe (2; 0.25 g, 1.05 mmol, 3.94 equiv.) in CH2Cl2
(5 mL), and the mixture was stirred for 5 min. Then, a solution of
iPrSH (40 mg, 0.5 mmol, 1.97 equiv.) in CH2Cl2 (0.85 mL) was
added dropwise over the course of 2 min. After 1 h at ambient tem-
perature, the mixture was concentrated under reduced pressure.
Chromatographic purification (silica gel, hexane/EtOAc = 8:1 to
2:1, Rf = 0.04 in hexane/EtOAc = 8:1) was followed by a second
chromatographic purification (silica gel, pentane/ether = 1:1, Rf =
0.19), which afforded the pure product (30 mg, 37%) as a red crys-
talline solid, m.p. 155–156 °C. 1H NMR (400 MHz, CDCl3): δ =
7.99 (s, 1 H, C5H), 7.55 (d, J = 4.6 Hz, 1 H, C7H), 7.30 (d, J =
4.0 Hz, 1 H, C1H), 6.73 (d, J = 4.2 Hz, 1 H, C2H), 6.70 (d, J =
4.6 Hz, 1 H, C6H), 2.97 (s, 3 H) ppm. 13C NMR (101 MHz,
CDCl3): δ = 157.4 (C8), 145.8 (C5), 137.9 (q, J = 40.2 Hz, C3),
134.7 (C8CNβ), 134.5 (C8CNα), 131.2 (m, C7), 122.8 (m, C1), 120.9
(dd, J = 5.1, 2.5 Hz, C6), 120.44 (q, J = 270.0 Hz, C3CF3), 116.1
(td, J = 3.9, 2.1 Hz, C2), 20.6 (C8SCH3) ppm. 19F NMR (376 MHz,
CDCl3): δ = –60.3 (t, J = 11.5 Hz, 3 F, CF3), –145.1 (Ψqq, J =
27.9, 11.7 Hz, 2 F, BF2) ppm. 11B NMR (128 MHz, CDCl3): δ =
0.1 (t, J = 27.8 Hz, BF2) ppm. 15N NMR (40.6 MHz, CDCl3): δ =
181.4 (Nα), 202.0 (Nβ) ppm. HRMS (ESI): calcd. for
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C11H8BF5N2NaS 329.0316 [M
C11H8BF5N2S (306.06): calcd. C 43.17, H 2.63, N 9.15; found
C 42.90, H 2.92, N 8.87.
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Received: July 7, 2014
Published Online: September 8, 2014
Eur. J. Org. Chem. 2014, 6371–6375
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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