Diversity-oriented derivatization of BODIPY based on regioselective bromination

Article abstract of DOI:10.1039/c2ob07004a

Regioselectively brominated BODIPYs were shown to undergo nucleophilic substitution and Sonogashira coupling reactions with a one-pot procedure, yielding diversely substituted fluorophores. The Royal Society of Chemistry 2012.

Full text of DOI:10.1039/c2ob07004a

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Diversity-oriented derivatization of BODIPY based on regioselective
bromination†
Xin Li, Shufang Huang and Yongzhou Hu*
Received 29th November 2011, Accepted 25th January 2012
DOI: 10.1039/c2ob07004a
2-carboxyaldehyde, followed by treatment with boron trifluoride
Regioselectively brominated BODIPYs were shown to
undergo nucleophilic substitution and Sonogashira coupling
reactions with a one-pot procedure, yielding diversely substi-
tuted fluorophores.
etherate.10
Initially, 1 was treated with bromine (Br2). Unlike the recent
report that 8-phenyl-BODIPY undergoes efficient stepwise bro-
mination with bromine,11 our reaction resulted in a mixture of
products hard to purify chromatographically, maybe due to the
4,4-Difluoro-4-bora-3a,4a-diaza-s-indacene (BODIPY) dyes rep-
resent a class of extremely popular fluorophores with various
valuable properties, such as excellent thermal and photochemical
stability, high and environment-independent fluorescence
quantum yields, narrow emission bandwidth, good solubility and
chemical robustness.1,2 They have been widely applied as label-
ing reagents for biomolecules,3 fluorescent switches,4 chemosen-
sors,5 and laser dyes.6 This remarkable versatility has sparked
intense research on new modification strategies to enable linking
to biological substrates and also to tune their optical properties.
Several new tactics for BODIPY functionalization have been
developed,7–9 among which, halogenation of the BODIPY core
is of primary importance because the introduction of a halogen
atom onto the BODIPY core facilitates further diverse derivatiza-
tion through (i) aromatic nucleophilic substitution8 or (ii) palla-
dium-catalyzed coupling reactions.9 These two types of reactions
exhibit different regioselectivities in that the former is confined
exclusively to α-halogenated BODIPYs, while the latter is appli-
cable to both α- and β-BODIPY halides (Scheme 1). Hence, the
application of these reactions in tandem to a single multi-haloge-
nated BODIPY would provide an access to more sophisticated
structures. However, no such methodology has been established.
The objective of the present work was therefore to develop a
facile method for diversity-oriented derivatization of regioselec-
tively brominated BODIPYs through a cascade of nucleophilic
substitutions and Sonogashira couplings.
1
more electron-rich nature of 1.11 Fortunately, H-NMR spectra
analysis of the mixture showed the inclusion of mono-, di- and
tri-brominated products, implying that stepwise dipyrrin bromi-
nation might be possible using a more mild brominating agent.
The reaction was then attempted with N-bromosuccinimide, but
this was also unsuccessful. Next, benzyl triethyl ammonium per-
bromide (2) was explored. Much to our delight, treating com-
pound 1 in dichloromethane with one equiv of 2 at 0 °C yielded
the mono-brominated product 3 almost quantitatively. Under
similar conditions, 3 could be transformed into the di-brominated
derivative 4 efficiently, and 4 could be further brominated to
yield the tri-brominated BODIPY 5 (Scheme 1). Compounds 4
and 5 can also be obtained in a straightforward way by direct
bromination of 1 with the proper amount of 2 with high yields
(98% and 96%, respectively) (ESI†).
The exact structures of the products were identified by 2D
NMR spectra analysis. The strong correlations of 1- and 3-
methyl protons (δ 2.24, 2.61) to a quaternary carbon atom
Our study started with 1,3-dimethyl-BODIPY (1) since it rep-
resents the simplest stable structure free of substituents at the α-
and β-positions.1 Compound 1 was synthesized by a classical
route through condensation of 2,4-dimethylpyrrole and pyrrole-
ZJU-ENS Joint Laboratory of Medicinal Chemistry, College of
Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058,
China. E-mail: huyz@zju.edu.cn; Tel: +86-571-88208460
†Electronic supplementary information (ESI) available: Synthetic
methods, spectral data, NMR and HRMS traces for all the new com-
pounds. See DOI: 10.1039/c2ob07004a
Scheme 1 IUPAC numbering system for BODIPY core and stepwise
bromination of 1 with PhCH2N+Et3Br3− (2).
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Table 1 Nucleophilic substitutions of 4–5 in benzene at room
temperature
Product
6a
Nucleophilea (R2H)
Piperidine
R2
Yield (%)
98
95
97
93
90
6b
Diethylamine
Benzenethiol
Piperidine
6c
7a
7b
Diethylamine
Scheme 2 Proposed mechanism for the stepwise bromination of 1.
The reaction is supposed to be an electrophilic bromination–oxidative
nucleophilic substitution–electrophilic bromination process. The first
bromination step is the basis for the second step because the electron
withdrawing effect of 2-bromine makes the σH-adduct exist long enough
to be oxidized and transformed to 4.
a At least two equiv N centred nucleophile were needed for the reaction
to proceed fast. While for “sulfur” centred nucleophile, one equiv Et3N
was required to work as a basic catalyst.
for the nucleophilic substitution of α-chlorinated BODIPY,8
treatment of compound 5 in acetonitrile with 2 equiv piperidine
at room temperature failed to yield the expected product 6a. A
variety of experimental conditions were tried. It was finally
revealed that the solvent was of crucial importance. Nonpolar
solvents, such as benzene or toluene, were favored, in which the
reaction was rapid at room temperature to furnish 6a approxi-
mately quantitatively. However, polar solvents, e.g. DMF,
acetone or methanol, led to decomposition of compound 5
slowly in the presence of the nucleophile. Other nucleophiles,
such as diethylamine or the S-based nucleophile, benzenethiol,
were next tried under the optimized reaction conditions and all
gave good results. Likewise, nucleophilic substitutions of com-
pound 4 were also carried out smoothly in benzene to furnish
the corresponding products in good yields (Table 1).
(δ 111.12, C-2) in the HMBC spectrum of 3 indicated the struc-
ture to be 2-bromo-1,3-dimethyl-BODIPY. The cross-peak
between H-6 (δ 7.56) and a quaternary carbon atom at δ 111.12
(C-5) in the HMBC spectrum of 4 indicated that the second
bromine atom was attached to the 5-position. Accordingly, the
correlation of H-7 (δ 6.94) to a quaternary carbon atom (δ
127.91, C-6) in the HMBC spectrum of 5 showed that the 6-pos-
ition was the site for the third bromination (ESI†).
This regioselectivity in the stepwise brominations may be
explained by an electrophilic bromination–oxidative nucleophilic
substitution–electrophilic bromination process (Scheme 2). Com-
pound 1 is intrinsically electron rich and so will readily undergo
electrophilic substitution reactions.1 Its 2-position, which is the
most nucleophilic owing to the electron-donating effect of the
neighboring methyl groups, is therefore the most susceptible to
The above nucleophilic substitutions of 4–5 proceeded so
rapidly and efficiently that it inspired us to carry out the nucleo-
philic substitution and Sonogashira coupling in the same way.
The regioselectivity of the two reactions may be ensured by their
greatly different rates.
−
electrophilic attack by the polarized PhCH2N+Et3Br3 complex
to produce the mono-brominated product 3. The unsubstituted
α-position of 3 is so positively-charged due to the electron-with-
drawing inductive effect of N, 4-F, and 2-Br that it is nucleophi-
lically attacked by Br−, forming a σH-adduct.12 Affected by the
electron withdrawing effect of 2-bromine, this adduct exists long
enough to be oxidized by 2 and transformed instantly to 4.
Further electrophilic bromination at the least positive charged 6-
position of 4 gives 5. This mechanism is supported by Mulliken-
charge analysis performed using Gaussian 09.
After successful synthesis of the desired multi-brominated
dyes, we next set out to explore a strategy for diversity-orientated
derivatization of 4 and 5 first through aromatic nucleophilic sub-
stitution at the 5-position and then via Sonogashira cross-coup-
ling at the 6- (or 2-) position.
To this end, compound 5, together with one equiv of a nucleo-
phile (R2H), was subjected to standard Sonogashira conditions.
As expected, compound 5 was reactive in benzene (containing
10% Et3N) at 60 °C, resulting in products which were nucleophi-
lically substituted at the 5-position as well as coupled with the
alkynyl (R3H) at the 6-position (compounds 8a–8d, Table 2).
This regiochemistry for Sonogashira coupling with priority for
the 6-position over the 2-position may be attributed to the steric
hindrance of the 2-position due to the neighboring methyl
groups. More forcing conditions, namely increasing the amount
of alkyne, elevating the reaction temperature and prolonging the
reaction time, allowed Sonogashira coupling to take place at both
the 6- and 2-positions, producing multi-derivatized compounds
9a–9c with fair yields (Table 2). Benzenethiol as a typical
Piperidine was tried first as a nitrogen-centered nucleophile to
attack tri-brominated BODIPY 5. Under the reported conditions
2370 | Org. Biomol. Chem., 2012, 10, 2369–2372
This journal is © The Royal Society of Chemistry 2012

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Table 2 One-pot synthesis of diversely substituted BODIPYs starting
from compound 5
Table 4 Absorption and emission profiles of 7b (red dash) and 9a
(blue solid), and optical properties of compounds 3–10 in CH2Cl2 at rta
Producta
8a
R1
Br
Br
Br
Br
R2
R3
Yield (%)
b
72
70
68
69
55
50
53
8b
8c
8d
Compd
λabs (nm)
ε (M−1 cm−1
)
λem (nm)
Φb (%)
9a
3
4
5
517
525
535
563
567
546
510
510
562
578
552
570
589
585
570
527
526
76 500
63 700
76 500
83 200
82 100
86 200
80 500
81 400
82 400
86 900
82 600
84 600
85 700
86 000
86 300
85 400
84 800
528
544
552
586
590
578
558
556
592
606
596
606
620
620
608
574
568
0.13
0.08
0.10
0.36
0.33
0.30
0.31
0.28
0.40
0.36
0.32
0.32
0.56
0.54
0.53
0.50
0.49
9b
9c
6a
6b
6c
7a
7b
8a
8b
8c
8d
9a
9b
9c
10a
10b
a To obtain compounds 8a–8d, one equiv nucleophile (R2H) plus two
equiv alkyne (R3H) were needed, and the reactions proceeded in
benzene (containing 10% Et3N) at 60 °C for 6 h. While for 9a–9c, one
equiv nucleophile (R2H) plus four equiv alkyne (R3H) were needed, and
the reactions took place in toluene (containing 10% Et3N) at 90 °C for
10 h. b For compound 9c, one equiv EtONa was used as the nucleophile.
Table 3 Multi-derivatization of compound 4 in a one-pot way
a Determined in CH2Cl2 (not degassed) solution, ca. 1 × 10−6 M.
b Quantum yields were accomplished by comparison with fluorescein (Φ
0.95, in 0.1 M NaOH) with the following equation where ∑[F] is the
integrated fluorescence intensity, Abs is absorbance at λex 496 nm, and n
represents the refractive index. For CH2Cl2 and 0.1 M NaOH, we used
refractive indices of 1.424 and 1.335 respectively. Φsample
Φ
=
standardAbsstandardΣ[Fsample](nsample)2/Abssample/Σ[Fstandard]/(nstandard)2.
Product
10a
R1
R2
Yield (%)
68
66
atom (N, O, or S) at the 5-position results in a remarkable red-
shift (∼30 nm), due to the p–π conjugation effect. Extension of
the π-electron conjugation by the attachment of alkynyl groups
at the 6- (7-) position also induces a bathochromic-shift.
10b
In short, we have established a facile one-pot method for the
fast construction of diversely substituted BODIPYs based on the
efficient regioselective bromination of 1,3-dimethyl-BODIPY.
This strategy will not only facilitate the modification of the dyes’
solubility and spectroscopic properties, but enable their easy
linkage to biomolecules or other groups of interest.
‘sulfur’ centred nucleophile was also tried in this method.
Although compound 6c was formed efficiently, as shown by
TLC analysis, it failed to couple with the alkyne. This may be
due to the inactivation effect of the sulfur atom on the Pd(0) cat-
alyst. Similarly, compound 4 also showed good reactivity under
this one-pot condition, giving 10a–10b in moderate yields
(Table 3).
Photophysical data of the diversely substituted BODIPYs in
dichloromethane are summarized in Table 4. All the compounds
show long wavelength emissions and the profiles are clearly sen-
sitive to the extent of electron delocalization over the skeleton.
Compounds 3–5 exhibit low quantum yields imparted by the
heavy atom effect13 and redshifted emission features that grow
with increasing dipyrrin bromination. Incorporation of a hetero
Acknowledgements
This work was supported by National Natural Science Foun-
dation of China (30901858), Zhejaing Provincial Natural
Science Foundation of China (Y2100580), China Postdoctoral
Science Foundation (201003735), the Fundamental Research
Funds for the Central Universities, and the State Key Laboratory
of Drug Research (SIMM1004KF-13).
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