Synthesis of 3,5-dichloro-4,4-difluoro-4-bora-3a,4a-diaza-s-indacenes (BODIPYs) via Cu(OTf)2 mediated oxidative nucleophilic substitution of hydrogen by chloride

Article abstract of DOI:10.1016/j.tet.2020.131113

Regioselective halogenation is often a key step in the formation of substituted 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (BODIPY) fluorophores, through the enablement of subsequent downstream C–C or C-X bond forming steps via S_NAr or metal ca

Full text of DOI:10.1016/j.tet.2020.131113

Journal Pre-proof
Synthesis of 3,5-dichloro-4,4-difluoro-4-bora-3a,4a-diaza-s-indacenes (BODIPYs) via
Cu(OTf) mediated oxidative nucleophilic substitution of hydrogen by chloride
2
Felicity Frank, Laura Manzoli Alice, Phillip Mauker, Abdulrahman A. Alsimaree, Paul
Gordon Waddell, Michael Richard Probert, Thomas James Penfold, Julian Gary
Knight, Michael John Hall
PII:
S0040-4020(20)30234-9
https://doi.org/10.1016/j.tet.2020.131113
TET 131113
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 22 January 2020
Revised Date: 26 February 2020
Accepted Date: 6 March 2020
Please cite this article as: Frank F, Alice LM, Mauker P, Alsimaree AA, Waddell PG, Probert MR,
Penfold TJ, Knight JG, Hall MJ, Synthesis of 3,5-dichloro-4,4-difluoro-4-bora-3a,4a-diaza-s-indacenes
(BODIPYs) via Cu(OTf) mediated oxidative nucleophilic substitution of hydrogen by chloride,
2
Tetrahedron (2020), doi: https://doi.org/10.1016/j.tet.2020.131113.
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Ar
B
Ar
B
ONSH with Cl
N
N
N
N
Cu(OTf)2
ethanolamine
TBAC
H
H
Cl
Cl
F
F
F
F
6 examples
31-99% yield

Synthesis of 3,5-Dichloro-4,4-difluoro-4-bora-3a,4a-diaza-s-indacenes (BODIPYs) via
Cu(OTf)2 Mediated Oxidative Nucleophilic Substitution of Hydrogen by Chloride
Felicity Frank,a Laura Manzoli Alice,a,b Phillip Mauker,a,c Abdulrahman A. Alsimaree,a,d Paul
Gordon Waddell,a Michael Richard Probert,a Thomas James Penfold,a Julian Gary Knighta*
and Michael John Halla*
a Chemistry, School of Natural and Environmental Sciences, Newcastle University,
Newcastle upon Tyne, NE1 7RU, UK
b Escola de Ciências da Saúde e da Vida, Pontifícia Universidade Católica do Rio Grande do
Sul (PUCRS), Brazil
c Faculty for Chemistry and Pharmacy, Ludwig-Maximilians-Universität München,
Butenandtstrasse 5-13, 81377, München, Germany
d Department of Basic Science (Chemistry ), College of Science and Humanities, Shaqra
University, Afif, Saudi Arabia
Abstract
Regioselective halogenation is often a key step in the formation of substituted 4,4-difluoro-4-
bora-3a,4a-diaza-s-indacene (BODIPY) fluorophores, through the enablement of subsequent
downstream C-C or C-X bond forming steps via SNAr or metal catalyzed cross-coupling
reactions. Classical SEAr halogenation of unsubstituted BODIPYs results in 2/6-substitution,
precluding easy access to 3/5-halogenated BODIPYs. Herein we present our development of
a 3,5-dihalogenation reaction of unsubstituted BODIPYs, via a double oxidative nucleophilic
substitution of hydrogen with chloride. Reaction of a range of meso-aryl, but otherwise
unsubstituted, BODIPYs with stoichiometric Cu(OTf)2 in the presence of ethanolamine and
tetrabutylammonium chloride gives high isolated yields of the corresponding 3,5-
dichlorinated BODIPYs, facilitating access to these valuable synthetic intermediates.
Introduction
Since their initial discovery in 1968 the 4,4′-difluoro-4-bora-3a,4a-diaza-s-indacene
(BODIPY) dyes have become a ubiquitous class of fluorophores (e.g. dye sensitized solar
cells, laser dyes, biological imaging agents and displays).1,2 Their popularity results from the
1

beneficial combination of superior photophysical properties (high fluorescence quantum
yields, extinction coefficients and photostability) and the availability of reliable synthetic
strategies for their construction and/or regioselective functionalization (Figure 1).3
Figure 1. Core structure and IUPAC numbering system for the 4,4-difluoro-4-bora-3a,4a-
diaza-s-indacene (BODIPY) fluorophores (Note: the 8-position is also commonly referred to
as the meso-position).
A common strategy in the synthesis of functionalized BODIPYs involves the initial
formation of the core fluorophore (typically via condensation chemistry) followed by
regioselective mono- or polyhalogenation. The thus formed halo-BODIPYs are valuable
synthetic intermediates capable of further transformation through C-C or C-X bond forming
reactions, such as metal catalyzed cross-coupling or nucleophilic aromatic substitutions
(SNAr).3 Electrophilic halogenation (SEAr) of unsubstituted BODIPYs results in preferential
2/6-substitution, steric blocking being required to access alternative regiochemistries
(Scheme 1: (a)).4 Thus improved access to the more synthetically elusive 3/5-halogenated
BODIPYs would be of significant interest, as they are important intermediates in the
synthesis of both red-shifted5 and chiral BODIPYs architectures.6 Synthetic access to the 3/5-
halogenated BODIPYs typically involves the electrophilic halogenation (SEAr) of the
BODIPY precursor dipyrromethanes, followed by oxidation to the corresponding
dipyrromethene and boron chelation (Scheme 1: (b)).7 However, this reaction sequence is oft
capricious due to competing oxidation of the dipyrromethane by the halogenating agent (e.g.
NBS) leading to complex product mixtures. Recently a number of new approaches to
BODIPY functionalization have been disclosed including direct palladium-catalyzed C–H
arylation,8 radical C-H funtionalization,9 vicarious nucleophilic substitution (VNS)10 and
oxidative nucleophilic substitution of hydrogen (ONSH).11 In particular Jiao et al. have
described a high yielding oxidative 3/5-selective mono-chlorination of BODIPYs using
stoichiometric CuCl2·2H2O. However extension of this methodology to the synthesis of 3,5-
dichlorinated BODIPYs gave only moderate yields (approx. 60%), which further reduced
with increased reaction times and/or the addition of excess CuCl2·2H2O (Scheme 1:(c)).12
2

Scheme 1. Regioselective halogenation of BODIPYs: (a) 2/6-halogenation via SEAr; (b)
3/5-halogenation via, stepwise SEAr halogentation of precursor dipyrromethenes, oxidation
and boron chelation; (c) 3/5-halogenation by oxidative nucleophilic substitution of hydrogen.
Results and Discussion
Due to our ongoing interest in the use of 3,5-dihalogenated BODIPYs as synthetic
intermediates,6 we decided to reexamine the copper mediated double oxidative nucleophilic
substitution of hydrogen (ONSH) with chloride, in order to develop an improved and high
yielding route to 3,5-dichlorinated BODIPYs. Thus, starting from meso-aryl BODIPY 1a, we
have investigated the oxidative 3,5-dichlorination of the BODIPYs in the presence of
stoichiometric copper salts (Table 1).
Table 1. Optimization of the copper mediated double ONSH with chloride reaction of
BODIPY 1a to give 3,5-dichloro BODIPY 3a.
Entry Copper Source
Additives
Ligand Time/min
Yield 3a
(%)
Yield 4a
(%)
a
3 eq. CuCl2·2H2O
10 eq.
-
-
0
0
360
60
-
-
-
1
2
29
3

CuCl2·2H2O
10 eq.
-
-
-
-
-
2 eq.
Phen
1 eq.
ETA
2 eq.
ETA
2 eq.
ETA
2 eq.
ETA
90
60
60
90
90
-
-
-
-
-
-
3
4
5
6
7
CuCl2·2H2O
10 eq.
57
67
69
63
CuCl2·2H2O
10 eq.
CuCl2·2H2O
10 eq.
CuCl2·2H2O
5 eq.
CuCl2·2H2O/
5eq. Cu(OTf)2
5 eq.
-
2 eq.
ETA
110
99
-
8
CuCl2·2H2O/
5eq. Cu(OTf)2
10 eq. Cu(OTf)2
5 eq.
TBAC
5 eq.
2 eq.
ETA
2 eq.
ETA
2 eq.
ETA
2 eq.
ETA
2 eq.
ETA
2 eq.
ETA
0
110
240
240
240
1800
110
110
110
110
96
49
-
9
10 eq. Cu(OTf)2
10 eq. Cu(OTf)2
10 eq. Cu(OTf)2
10 eq. Cu(OTf)2
10 eq. Cu(OTf)2
10 eq. Cu(OTf)2
10 eq. Cu(OTf)2
10 eq. Cu(OTf)2
20
9
10
11
12
13
14
15
16
17
TBAC
2 eq.
20
TBAC
5 eq.
59b
63b
77c
37
10
15
2
TBAC
5 eq.
TBAC
5 eq.
TBAC
5 eq.
TBAC
5 eq.
2 eq.
ETA
2 eq.
ETA
61d
51d,e
TBAC
5 eq.
TBAC
4

10 eq. Cu(OTf)2
5 eq.
2 eq.
ETA
110
95e
18
TBAC
Reactions carried out on a 0.15 mmol scale in MeCN (6 mL); a) 3-chloro-BODIPY 2a
isolated in 62% yield; b) Reactions carried out at 60 oC; c) 1.4 mmol scale (i.e. 460 mg of
BODIPY 1a; d) Reaction carried out under an atmosphere of nitrogen; e) Ambient light
excluded. Phen = 1,10-phenanthroline, ETA = ethanolamine, TBAC = tetrabutylammonium
chloride.
Initial examination of the copper mediated double ONSH with chloride of BODIPY 1a
were based on Jiao’s conditions, involving stoichiometric quantities (3 equivalents) of
CuCl2·2H2O in refluxing acetonitrile under an atmosphere of air for 6 hours. However in our
hands no conversion to the desired 3,5-dichloro BODIPY 3a was observed, although 3-chloro
BODIPY 2a could be recovered in moderate yield (62%). Increasing the stoichiometry of
CuCl2·2H2O (10 eq.) did result in the isolation of the desired 3,5-dichloro BODIPY 3a albeit
in a low yield of 29%, however attempts to improve the yield of 3,5-dichloro BODIPY 3a,
either through extended reaction times or further increases in the equivalents of CuCl2·2H2O
failed, in line with Jiao’s original observations (Table 1, entries 1 and 2).
We postulated that these low conversions may be in part due to the poor solubility of
CuCl2·2H2O in acetonitrile, prompting us to examine the use of copper chelating ligands. The
addition of 2 equivalents of 1,10-phenanthroline to the dichlorination reaction resulted in
complete inhibition of the desired ONSH chemistry, even with extended reaction times
(Table 1, entry 3), however significant improvements in yield were obtained through the
addition of 1 equivalent (57%) or 2 equivalents (69%) of ethanolamine (Table 1, entries 4-6).
Alternate Cu2+ sources were also examined, the use of a 1:1 mixture of 5 eq. CuCl2·2H2O and
5 eq. Cu(OTf)2 giving a similar yield of target 3,5-dichloro BODIPY 3a (63%), which
improved (99%) following an extended reaction time of 110 minutes (Table 1, entries 7-8).
Complete replacement of CuCl2·2H2O with 10 eq. of Cu(OTf)2 was also examined, with the
addition of 5 eq. of tetrabutylammonium chloride acting as a chloride source, providing a
near quantitative yield (96%) of 3a (Table 1, entry 9).
Extended reaction times (4 hours) resulted in a decrease in isolated 3a (49 %) due to the
1
formation of trichloro-BODIPY 4a in 20 % yield (Table 1, entry 10). H NMR coupling
constant analysis and 1D-NOESY experiments supported a 2,3,5-trichloro-substitution
5

pattern for BODIPY 4a, which was confirmed by single crystal X-ray diffraction analysis
following crystallization from a DCM solution (Figure 2).13 We postulate that 2,3,5-trichloro-
BODIPY 4a forms from 3,5-dichloro-BODIPY 3a, through an SEAr reaction with chlorine,
itself formed in situ by copper mediated oxidation of chloride.
Figure 2: X-ray crystal structure of 2,3,5-trichloro-BODIPY 4a.
o
The use of 2 eq. of TBAC, or lower reaction temperatures (60 C) in combination with
extended reaction times (Table 1, entry 11-13) gave no further improvement in the isolated
yield of 3a. Our optimized conditions also proved scalable, allowing approximately 0.5
grams of 3,5-dichloro-BODIPY 3a to be prepared in a single reaction (Table 1, entry 14).
To gain further additional insight into our optimized dichlorination conditions, we carried
out a series of control experiments (Table 1, entries 15-18). Omission of ethanolamine lead to
significant drops in the isolated yield of BODIPY 3a. The use of a nitrogen atmosphere also
resulted in decreased yields, suggesting a role of atmospheric oxygen in the reaction, perhaps
through the oxidative recycling of an active copper species. Whilst photochemical reaction
pathways could be excluded, as no change in yield is observed when the reaction is carried
out in the dark.
Finally, it should be noted that during the optimization of the synthesis 3,5-dichloro-
BODIPY 3a a number of crystallization experiments were undertaken in order to grow single
crystals suitable for X-ray diffraction analysis.13 This resulted in the determination of two
different crystal structures for 3,5-dichloro-BODIPY 3a, one corresponding to a known
monoclinic C2/c polymorph (CSD: XEBZIQ),14 whilst a second was shown to be a new
monoclinic P21/c polymorph. Together with a previously reported triclinic P-1 polymorph
(CSD: XEBZIQ01),15 this brings the total number of known polymorphs for this compound
to three. Interestingly, the three polymorphic forms show little conformational variation in the
6

individual molecules of 3a but do show considerable differences in their π···π stacking,
resulting in three distinct dimeric units within the crystal structures, each displaying differing
levels of overlap of their conjugated cores (Figure 3 and ESI).
Figure 3: Comparison between the molecules of 3a, composing the dimeric unit in each of
the three polymorphs shown [P-1 polymorph (CSD: XEBZIQ01), P21/c polymorph (this
work)13 and C2/c polymorph (CSD: XEBZIQ)].
Next we sought to apply our optimized oxidative 3,5-dichlorination methodology to a more
extensive range of meso-aryl substituted BODIPYs (Table 2). Synthesis of BODIPYs (1b-f)
was carried out as previously (see SI), followed by double ONSH with chloride under our
previously optimized conditions. Excellent yields were obtained in the case of 3,5-dichloro-
BODIPYs (3a-c), which contained electron deficient meso-aryl groups (Table 2, entries 1-3).
However, lower yields (31 %) were observed in the case of ortho-tolyl substituted BODIPY
(3d), potentially through competing chlorination of the tolyl group leading to complex
product mixtures. In the case of BODIPYs with electron rich meso-aryl groups (3e-f)
moderate yields were obtained, however these appear to be a consequence of slower rate of
reaction as yields could be improved (70%) with longer reaction times (Table 2, entries 4-7).
Table 2. Copper mediated double ONSH with chloride of BODIPYs 1(a-f).
10 eq. Cu(OTf)2
5 eq. TBAC
2 eq. ETA
Ar
Ar
N
N
N
N
MeCN
reflux
B
B
Cl
Cl
F
F
F F
1(a-f)
3(a-f)
7

Entry
Ar
Reaction
Time/min
110
Product
Yield (%)
4-(MeCO2)C6H4 (1a)
4-(NO2)C6H4 (1b)
3-(NO2)C6H4 (1c)
2-(CH3)C6H4 (1d)
4-(MeO)C6H4 (1e)
3-(MeO)C6H4 (1f)
3-(MeO)C6H4 (1f)
96 %a
92 %
99 %
31 %
66 %
56 %
70 %
1
2
3
4
5
6
7
3a
3b
3c
3d
3e
3f
110
110
110
110
110
150
3f
Reactions carried out on a 0.14-0.25 mmol scale in MeCN (5-6 mL); a) reproduced from
table 1 for comparison.
It is notable that the double ONSH with chloride of our BODIPY systems appears to
proceed more rapidly for cases containing an electron deficient meso-aryl group. In the case
of BODIPYs 1a-c and 1e-f the meso-aryl groups can obtain near co-planarity with the
conjugated core, and as such have a significant impact on the electronics of the BODIPY. To
further explore this the energy levels of the HOMOs and LUMOs of 1a-c and 1e-f were
calculated using density functional theory (DFT) within the approximation of the PBE0
exchange and correlation functional16 as implemented within the Q-Chem quantum chemistry
package,17 employing a Def2-SVP basis set.18 For these para- and meta- substituted meso-
aryl BODIPYs (1a-c and 1e-f) the observed yields (at 110 minutes) correlate well with the
calculated energies of the LUMO’s (see SI), more rapid chlorination occurring for those
compounds with low energy LUMOs. Interestingly this observation appears to contradict the
Jiao mechanism,12 in which the rate determining step is likely the oxidation of the BODIPY
to the corresponding radical cation by Cu2+.
In conclusion, we have developed a robust and high yielding double ONSH with chloride
for the formation of 3,5-dichloro-BODIPYs with a range of meso-substituents. These 3,5-
dichloro-BODIPYs are valuable synthetic intermediates, capable of undergoing both
transition metal catalyzed couplings and nucleophilic aromatic substitutions (SNAr), in the
synthesis of 3,5-functionalised BODIPY architectures.
Acknowledgments
8

The authors thank Newcastle University (NCL) for funding a PhD scholarship (F.F.),
Shaqra University for PhD scholarship (A.A.A.), Dr. Corinne Wills and Prof. W. McFarlane
for NMR support at NCL, the EPSRC for X-ray crystallography facilities at NCL
(EP/F03637X/1), the EPSRC UK National Mass Spectrometry Facility at Swansea University
and Rebecca G. Clarke and Heinrich Von Koeller (NCL) for supporting studies.
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10

•
•
•
Regioselective 3,5-dichlorination of unsubstituted BODIPYs is achieved.
Double oxidative nucleophilic substitution of hydrogen with chloride.
High yields are obtained for a range of 3,5-dichloro meso-aryl BODIPYs.

Declaration of interests
☒ The authors declare that they have no known competing financial interests or personal relationships
that could have appeared to influence the work reported in this paper.
☐The authors declare the following financial interests/personal relationships which may be considered
as potential competing interests: