Development of BODIPY dyes with versatile functional groups at 3,5-positions from diacyl peroxides via Cu(ii)-catalyzed radical alkylation

Article abstract of DOI:10.1039/C9CC01602C

An efficient Cu(ii)-catalyzed, C-H alkylation of BODIPY with a variety of alkyl diacyl peroxides has been developed for the first time, providing a late-stage and straightforward method for controllable synthesis of monoalkylated and dialkylated BODIPYs via a radical process that otherwise is difficult to obtain by literature methods. This chemo- and site-selective transformation will allow for the introduction of a variety of functionalities on the BODIPY core for highly versatile tethering to receptors and to other molecules of interest.

Full text of DOI:10.1039/C9CC01602C

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DOI: 10.1039/C9CC01602C
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Development of BODIPY Dyes with Versatile Functional Groups at
3,5‐Positions from Diacyl Peroxides via Cu(II)‐Catalyzed Radical
Alkylation
Received 00th January 20xx,
Accepted 00th January 20xx
Bing Tang,a Fan Lv,a Kangkang Chen,a Lijuan Jiao*a Qingyun Liu,b Hua Wang,a and Erhong Hao*a
DOI: 10.1039/x0xx00000x
www.rsc.org/
An efficient Cu(II)‐catalyzed, C‐H alkylation of BODIPY with a
variety of alkyl diacyl peroxides has been developed for the first
time, providing a late‐stage and straightforward method for
controllable synthesis of monoalkylation and dialkylation BODIPYs
via radical process that otherwise difficult to obtain by literature
methods. This chemo‐ and siteselective transformation will allow
for the introduction of a variety of functionalities on the BODIPY
core for highly versatile tethering to receptors and to other
molecules of interest.
Since the initial report in 50 years ago, BODIPY (4,4’‐difluoro‐4‐
bora‐3a,4a‐diaza‐s‐indacene) dyes1 have been increasingly
used for various different applications, including labelling
reagents, chemosensors, therapeutic agents, energy transfer
cassettes, and so on.2,3 To a great extent BODIPY dyes owe
popularity to their excellent and facile tuneable photophysical
properties and their rich functionalization chemistry. Thus, in
order to control their photophysical properties, enable their
tagging to receptors and to other molecules of interest, it is
critical to introduce new functionalities for highly versatile
tethering in designing novel BODIPY derivatives.4‐6 For example,
Figure 1. (a) Commercialized BODIPY 576/589 A, reportedα‐alkylated BODIPYs
and ; (b) our regioselective methodology toward α‐alkylated BODIPYs.
B
C
most likely due to the lack of convenient synthetic methods.
Traditionally, most of BODIPYs with desired functional groups
have been synthesized through suitably prefunctionalized
pyrroles via acid promoted condensation. These available
synthetic methods involve multiple steps, and often require
the use of expensive catalysts. For example, BODIPY
B
developed by Kanie et. al5 and sensor
C
developed by Cosa et.
al6 were available in small quantities due to the complicated
synthesis and the use of expensive precursors (Scheme S1, ESI).
Given that the complicated and lengthy de nova synthesis
steps and the unstable nature of pyrrole derivatives, the
overall yields toward these advanced fluorescent probes is
extremely low.
alkylBODIPY
A (Figure 1a) with a free carbolic acid group
marketed by Introvigen as BODIPY 576/589 have been
commonly used as long wavelength biological labels. BODIPY
B5 (Figure 1a) with dual functionalities of carbolic acid and
azide groups can label biomacromolecules containing amine
groups such as glycosphingolipids and facilitate further isobaric
tagging via the “Click” reaction.
Despite the popularity of BODIPY based probes and sensors
used, however, BODIPY derivatives with versatile alkyl groups
(other than methyl) at their 3‐ or 3,5‐positions are limited,
Recently, the late‐stage diversification of structurally
complex molecules, including BODIPY dyes, bears enormous
potential for providing modular access to novel functional
substances.7 For example, Ackermann et. al recently reported
BODIPY peptide labeling by late‐stage C(sp3)‐H activation.7a
Here we describe a novel Cu(II) catalyzed, regioselective
alkylation of BODIPY core with various alkyl diacyl peroxides.
This reaction provides an efficient approach to a series of α‐
alkylated BODIPYs with diverse functionalities. Peroxides have
been reported as efficient and powerful alkylating agents via
radical alkylation in mild reaction condition. More importantly,
these peresters and diacyl peroxides are readily prepared from
a. The Key Laboratory of Functional Molecular Solids, Ministry of Education; School
of Chemistry and Materials Science, Anhui Normal University, Wuhu, China.
b. College of Chemistry and Environmental Engineering, Shandong University of
Science and Technology, Qingdao, China.
Email: haoehong@ahnu.edu.cn; jiao421@ahnu.edu.cn
Electronic Supplementary Information (ESI) available: Experimental details,
spectroscopic/photophysical properties, NMR and HRMS spectra for all new
compounds. CCDC 1903798, 1903800 and 1903801. For ESI and crystallographic
data in CIF or other electronic format, see DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
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Table 1. Optimization of the reaction conditions a
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DOI: 10.1039/C9CC01602C
entry
catalyst
(mol%)
solvent
temp.
(oC)
80
80
80
80
80
80
80
80
80
80
80
80
80
80
70
90
100
90
90
90
90
90
90
time
(h)
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
8
10
16
5
5
5
yields of
3a
%)b
(
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
Fe(OTf)3 (10)
FeCl3 (10)
Fe(OTf)2 (10)
Cu(acac)2 (10)
Cu(OAc)2 (10)
CuCl2 (10)
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
DMSO
DMF
CH3CN
1,2‐DCE
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
42
30
20
56
50
43
23
19
42
36
53
45
52
48
54
62
56
60
58
60
46
31
<5
CuCl (10)
CuBr (10)
Pb(OAc)2 (10)
AgOAc (10)
Cu(acac)2 (10)
Cu(acac)2 (10)
Cu(acac)2 (10)
Cu(acac)2 (10)
Cu(acac)2 (10)
Cu(acac)2 (10)
Cu(acac)2 (10)
Cu(acac)2 (10)
Cu(acac)2 (10)
Cu(acac)2 (10)
Cu(acac)2 (20)
Cu(acac)2 (5)
none
Scheme 1. Scope of the monoalkylation reaction of BODIPYs 1 and peroxides 2.
aReaction conditions: 1a (0.1 mmol), 2a (0.1 mmol). bYield of the isolated product.
abundant, inexpensive and versatile carboxylic acids8 and thus
represent an important source of alkylating agents through
decaboxylation.7b,9 Inspired by these previous works,7‐9 we
decided to investigate the possible alkylation10 of BODIPY dyes
using diacyl peroxides via radical reaction11 (Scheme 1b).
Initially, we took BODIPY 1a and Lauroyl peroxide (LPO) 2a
as model substrates to test this reaction (Table 1). The reaction
of 1a with 2a used Fe(OTf)3 (10 mol%) as the catalyst and PhCl
(1mL) as the solvent at 80 °C (Table 1, entry 1). A slightly less
polar product (than that of 1a) was formed which was
detected by TLC. After separation, this product named 3a was
isolated in 42% yield and was characterized by HRMS and NMR
characterizations. 1H NMR clearly indicated that the
monoalkylation exclusively took place at the
BODIPY core in BODIPY 3a with only one
α
‐position of the
α
‐proton signal at
7.77 ppm left. The regiochemistry of this reaction was further
Scheme 2. Scope of the dialkylation reaction of BODIPYs 1 and peroxides 2.
confirmed by X‐ray structure analysis of 3a (Fig. 2). Based on
this result, various catalysts were examined (entries 2−10), and
it was found that Cu(acac)2 was the most effective one, giving
a 56% yield of the desired product (entry 4). Next, various
temperature indicated that 90 °C was the most optimal one
(entry 16), giving 3a in 62% yield. This reaction is normally
complete in 5 h, which also can be easily tracked by
consumption of starting BODIPY 1a using TLC. Further
prolongation of the reaction time or variation of catalyst
solvents,
dimethylformamide
dichloroethane (1,2‐DCE), were evaluated (entries 4 and 10
including
Dimethyl
(DMF), acetonitrile
sulfoxide
(DMSO)
and
1,2‐
−
14)
loading does not result in an increased yield (entries 18
−23).
in the presence of Cu(acac)2. Chlorobenzene proved to be the
most suitable solvent. Further optimization of the reaction
Interestingly, the reaction is highly sensitive to the amount of
peroxide 2a used. By simply increasing the amount of 2a to 2
2 | J. Name., 2012, 00, 1‐3
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equiv, the 3,5‐dialkylation BODIPY 4a were obtained as the the regioselectivity of this α‐alkylation reaction. Similarly, the
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DOI: 10.1039/C9CC01602C
major product in 32% yields (Table S1, ESI). The structure of unsymmetrical 3‐chloroBODIPY 1f with highly reactive halogen
BODIPY 4a was confirmed by HRMS (calcd. 645.37197, and group (Cl‐) and one free α‐position (Scheme 3b), which was
found 645.37189). NMR spectra further provided the highly synthesized using 1.5 equiv CuCl2 in acetonitrile14, also showed
symmetrical nature of 4a. We then further applied meso‐ analogous regioselectivity in this radical alkylation reaction.
arylBODIPYs 1b containing electron withdrawing group and 1c The 3‐Cl group was tolerated in this reaction and the reaction
containing electron donating substituent (Figure S1, SI) with between BODIPY 1f and 1 equiv alkyl diacyl peroxides 2i gave
this optimized reaction condition. Monoalkylation BODIPYs 3m only one product 5c in 58% yield. Further application of 5c in a
and 3n were isolated in 72% and 65% yields, respectively. simple aromatic nucleophilic substitution (SNAr) using neat
Trace amount of dialkylation products with only 1 equiv 2a pyrrole15 also generated the corresponding BODIPY 5b in 40%
was also found in both reactions. By raising the ratio of 2a to 2 yield (Scheme 3b).
equiv, the corresponding the 3,5‐dialkylation BODIPYs 4m and
4n were obtained as the major products in 50% and 40% yields,
respectively (Scheme 2).
Next, we explored the substrate scope with various alkyl
diacyl peroxides that were selected based on the type of alkyl
radicals they generate under the optimized reaction condition
as shown in Schemes 1 and 2. Alkyl diacyl peroxides
2 were
prepared in one step from the corresponding carboxylic acids
(see ESI for details). We were pleased to find that these
peroxides gave the corresponding monalkylated products 3b‐
3l in 50%‐65% yields, respectively (Scheme 1). Similarly, in the
presence of 2 equiv of alkyl diacyl peroxides, the dialkylation
products were dominant in this reaction. A variety of
corresponding dialkylation BODIPYs 4b‐4l were obtained in 35‐
Figure 2. Top and front views of X‐Ray structures of BODIPYs 3a (a), 4e (b) and
crystal packing of BODIPY 4e (c). C, gray; N, blue; B, dark yellow; F, bright green;
Cl, light blue. Hydrogen atoms have been removed for clarity.
o
56% yields in the presence 0.1 equiv of Cu(acac)2 at 90 C
(Scheme 2). These resultant BODIPY dyes
3 and 4 contain
versatile functional groups, including halogens, alkenes,
alkynes, ketones and esters, which render further useful
transformation and tethering to receptors and other
molecules or biomacromolecules of interest via sophisticate
nucleophilic substitutions, thiol‐ene click, azide–alkyne click
and condensation reactions.12,13
In the crystal structures of BODIPYs 3a, 4e and 5a (Figure 2
and Scheme 3), the B‐N distances are within 1.52‐1.56 Å,
indicating the usual delocalization of the positive charge.
Each of these BODIPYs shows an almost planar central BN2C3
six‐membered ring where B atoms have slightly distorted
tetrahedron geometry. The angles between the two pyrrolic
rings in the dipyrrin core are 2.6o for 3a, 4.3o for 4e and 1.7o
for 5a (Table S2, ESI), respectively. The dihedral angles
between the meso‐2,6‐dichlorophenyl group and the dipyrrin
core are around 84o, 88o and 84o for 3a
, 4e and 5a,
respectively. The 3‐pyrrole substituent in 5a lies almost in the
same plane of the BODIPY core, with deviations of only 11.2o
(Scheme 3a). Intramolecular hydrogen bonds between the
hydrogen attached to the uncoordinated pyrrolic nitrogen and
the fluorine atoms in 5a were observed. The observed NH
distances were 2.09 and 2.39 Å. The intramolecular hydrogen
bonds and the observed short NH F distances may reduce
…F
…
the degree of rotation of the 3‐substituted pyrrole and
enhance the rigidity of the dyes. All BODIPYs exhibits well‐
ordered and slipped crystal stackings in head‐to‐tail
configuration, in which the interplanar distance of two
Scheme 3. Synthesis of BODIPYs 5a‐c
.
adjacent molecules is 3.43 Å, 3.80 Å, 3.60 Å for 3a, 4e and 5a,
respectively (Figure S2, ESI).
Finally, we further applied 3‐pyrrolylBODIPYs 1d and 1e with
highly active pyrrolic substituent to this reaction (Scheme 3a).
Interestingly, no alkylation on pyrrolic substituent of both
BODIPYs was found in this reaction. In the presence 1 equiv of
alkyl diacyl peroxides 2b and 2i, the corresponding α‐alkylated
products 5a and 5b were obtained in 62% and 65% yields,
respectively. X‐Ray structure of BODIPY 5a further confirmed
Control experiments were performed under the optimized
condition to gain insight into the mechanism of this reaction.
When radical scavenger, 0.5 equiv 2,2,6,6‐tetramethyl‐1‐
piperidinyloxy (TEMPO), were introduced into the standard
reaction of BODIPY 1a and LPO 2a, desired product 3a in 15%
yield was obtained. No reaction was detected by increasing the
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regiochemistry of this alkylation is in agreement with
previously reported radical reactions on BODIPYs.11
Preliminary spectroscopic properties of these newly
synthesized BODIPYs were investigated in dichloromethane
and were summarized in Table S3 (ESI). Overall typical BODIPY
features were obtained for these dyes, which are similar to
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their corresponding starting BODIPYs 1. Their absorption and
emission maxima showed around 10 nm red shifts with each
alkyl group installed. For example, monoalkylation BODIPY 3b
has maximum absorption at 516 nm, while dialkylation 4b red‐
shifts to 524 nm. Particularly, the absorption and emission
maxima of BODIPY 5a showed further red‐shifts to 600 nm and
3
4
620 nm (Figure 3a). Most of these BODIPYs
comparable or even superior fluorescence quantum yields
comparing to their starting BODIPYs . In addition, BODIPYs 4e
3‐5 show
1
and 4f also showed good solid‐state fluorescence (Figure 3b).
The emission maxima at 662 and 634 nm in the solid powder
state are around 120 and 93 nm red‐shifted compared with
their corresponding emissions in dichloromethane, with the
absolute quantum yields of 0.51 and 0.28, respectively. The
high solid‐state fluorescence of these BODIPYs is in good
agreement with their crystal‐packing structures. For example,
BODIPY 4e adopted coplanar inclined arrangement of its
transition dipole with slip angles of 42o (Figure 2c), which is
characteristic of J‐type packing consistent with Kasha’s
molecular exciton model.16
5
6
7
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400
400
450
500
550
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650
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800
500
600
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Wavelength (nm)
Wavelength
（
nm
）
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Figure 3. (a) Overlaid normalized absorption (solid lines) and fluorescence
emission (dashed lines) spectra of BODIPYs 3b, 4b and 5a in dichloromethane at
room temperature. (b) Normalized absorption (blue) and solution fluorescence
(red) in dichloromethane and solid‐state fluorescence (green, powder) spectra of
4e. The inset shows the photograph of the powder of 4e with UV irradiation at
360 nm.
In summary, an efficient C‐H alkylation of BODIPY with
variety of alkyl diacyl peroxides has been developed,17 allowing
for the facile synthesis of a broad range of structurally diverse
alkylated BODIPYs. This method exhibits excellent
chemoselectivity, affording exclusively α‐alkylated BODIPYs in
the presence of catalytic Cu(acac)2 via radical process. The
versatile functional groups of these alkylated BODIPY
fluorophores render further useful transformation, labeling
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This work is supported by the National Nature Science
Foundation of China (Grants Nos. 21672006, 21672007 and
21872002).
2010, 12, 4010; (b) S. Choi, J. Bouffard, Y. Kim, Chem. Sci., 2014, 5, 751.
17 See Scheme S2 in ESI for the comparation of this methodology with
previously method in ref. 11b.
Notes and references
4 | J. Name., 2012, 00, 1‐3
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DOI: 10.1039/C9CC01602C
Nucleophilic aromatic substitution of BODIPY  Radical alkylation
O
O
O
Alkyl
Alkyl
O
Alkyl
O
O
Alkyl
Ar
B
Ar
Ar
O
O
(1 equiv)
Cu(acac)2
PhCl, 90 oC, 5 h
(2 equiv)
Cu(acac)2
PhCl, 90 oC, 5 h
N
N
N
N
N
N
B
B
Alkyl
Alkyl
H
H
Alkyl
F F
F
F
F
F
Cu(II) catalyst, highly regioselective, no directing group, versatile products
Cu(II)-catalyzed, α-regioselective C-H alkylation of BODIPY with alkyl diacyl peroxides provide structurally diverse alkylated
BODIPYs via radical pathway.