Syntheses of o-iodobenzyl alcohols?BODIPY structures as potential precursors of bimodal tags for positron emission tomography and optical imaging

Article abstract of DOI:10.1016/j.tet.2019.130765

Aiming the faster development from bench to bedside of new potential tracers, multimodal tracers for positron emission tomography (PET) and optical imaging (OI) have emerged as a very promising tool. Indeed, they combine the simplicity of use of optical techniques for in vitro/in vivo pre-clinical studies with the various clinical possibilities offered by PET imaging using their radioactive versions. In this context, the preparation of new tags detectable by fluorescence imaging and potentially suitable for PET imaging after a last-step ¹¹C-labeling of the corresponding precursor has been investigated. Various designs and syntheses were explored by linking o-iodobenzyl alcohols and tetramethyl-BODIPY moieties together. Among them, the most promising structure was produced in 30% yield over five steps from a commercially available and inexpensive starting material.

Full text of DOI:10.1016/j.tet.2019.130765

Journal Pre-proof
Syntheses of o-iodobenzyl alcohols‒BODIPY structures as potential precursors of
bimodal tags for positron emission tomography and optical imaging
Thifanie Christine, Alexis Tabey, Thomas Cornilleau, Eric Fouquet, Philippe
Hermange
PII:
S0040-4020(19)31158-5
https://doi.org/10.1016/j.tet.2019.130765
TET 130765
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 25 July 2019
Revised Date: 31 October 2019
Accepted Date: 5 November 2019
Please cite this article as: Christine T, Tabey A, Cornilleau T, Fouquet E, Hermange P, Syntheses of o-
iodobenzyl alcohols‒BODIPY structures as potential precursors of bimodal tags for positron emission
tomography and optical imaging, Tetrahedron (2019), doi: https://doi.org/10.1016/j.tet.2019.130765.
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition
of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of
record. This version will undergo additional copyediting, typesetting and review before it is published
in its final form, but we are providing this version to give early visibility of the article. Please note that,
during the production process, errors may be discovered which could affect the content, and all legal
disclaimers that apply to the journal pertain.
©
2019 Published by Elsevier Ltd.

Graphical Abstract
.
Syntheses of o-iodobenzyl alcohols‒BODIPY
structures as potential precursors of bimodal
tags for positron emission tomography and
optical imaging.
Leave this area blank for abstract info.
Thifanie Christine, Alexis Tabey, Thomas Cornilleau, Eric Fouquet* and Philippe Hermange*
Univ. Bordeaux, CNRS, Bordeaux INP, ISM, UMR 5255, F-33400, 351, Cours de la Libération, 33405 Talence
Cedex, France.

1
Tetrahedron
journal homepage: www.elsevier.com
Syntheses of o-iodobenzyl alcohols‒BODIPY structures as potential precursors of
bimodal tags for positron emission tomography and optical imaging.
Thifanie Christine, Alexis Tabey, Thomas Cornilleau, Eric Fouquet* and Philippe Hermange*
Univ. Bordeaux, CNRS, Bordeaux INP, ISM, UMR 5255, F-33400, 351, Cours de la Libération, 33405 Talence Cedex, France.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Aiming the faster development from bench to bedside of new potential tracers, multimodal
tracers for positron emission tomography (PET) and optical imaging (OI) have emerged as a
very promising tool. Indeed, they combine the simplicity of use of optical techniques for in vitro
/ in vivo pre-clinical studies with the various clinical possibilities offered by PET imaging using
their radioactive versions. In this context, the preparation of new tags detectable by fluorescence
Available online
1
1
imaging and potentially suitable for PET imaging after a last-step C-labeling of the
corresponding precursor has been investigated. Various designs and syntheses were explored by
linking o-iodobenzyl alcohols and tetramethyl-BODIPY moieties together. Among them, the
most promising structure was produced in 30% yield over five steps from a commercially
available and inexpensive starting material.
Keywords:
Positron Emission Tomograpy
Fluorescence Imaging
Multimodal tracer
BODIPY
2
009 Elsevier Ltd. All rights reserved.
Carbonylation
+
1
. Introduction
Precision medicine” is a concept based on an individualized
desired biological target) with both a β emitter element and a
fluorophore, providing linear or tripodal molecules (Scheme
“
6
1
A).
therapeutic approach, which is particularly useful for
heterogeneous classes of diseases such as cancer. Indeed, i1t
provides access to a more optimized treatment for each patient,
but the use of advanced diagnostic tools, as for instance medical
imaging, is required by the clinician. Among the various imaging
techniques available, Position Emission Tomography (PET) is a
powerful method that localizes in vivo a radiotracer designed to
2
be specific for a biological process. However, the clinical
development of new PET-radiotracers is strongly hampered by
+
the short half-life of the β emitters mainly employed (109.8min,
18
11
68
2
0.4 min and 68.3 min for F, C and Ga, respectively), as
well as the technical constraints resulting from manipulating
radioactive materials. On the other hand, fluorescence detection
is an optical imaging technique (OI) that is much more
convenient in the translational process from chemical syntheses
3,4
to preclinical studies.
Unfortunately, despite 5being
therapeutically useful for fluorescence-guided surgery, the
limited light-permeability of the biological tissues prevents its
use for medical imaging in clinical diagnostics. Thus, developing
new structures that could be detected by both of these techniques
would be highly beneficial to speed up the development of new
potential tracers from bench to bedside. Indeed, such multimodal
PET/OI tracers would combine the simplicity of use of
fluorescent techniques for in vitro and pre-clinical studies, while
allowing in vivo localization in clinical experiments when
switching to their radioactive versions. This strategy has recently
been investigated by researchers, and relies in most cases on the
linking of a biomolecule (possessing a high affinity for the
Scheme 1. BODIPY-based PET/OI bimodal tracers: general
designs and examples. Peptide A: bombesin, Peptide B:
octreotide.
In particular, boron-dipyrromethene (BODIPY) cores have
been extensively employed as fluorescent moieties due to their
7
versatile syntheses and excellent optical properties. For instance,
they can provide radiotracers potentially suitable for PET after
18
8
activating the boron center and reacting it with [ F]fluoride.

2
Tetrahedron
Nevertheless, such strategy remains challenging for the last-step
labeling of highly functionalized biomolecules due to the high
reactivity of the activated precursors. On the other hand,
structures combining BODIPY cores to various ligands were also
explored as potential bimodal PET/IO tracers after coordination
coupling reaction for the proof of concept. Indeed, the azido-
BODIPY 3 was readily obtained in two steps from the
corresponding phthalide 1 using slightly modified conditions
16
from the literature, and it was coupled with the propargylated
12a
tag 4 in standard conditions to synthesize the desired conjugate
5 with a good yield of 73% (Scheme 3). Then, the reactivity of 5
in Pd-catalyzed carbonylation was confirmed using model
+
9
to a metallic β emitter (Scheme 1B). In this case, the labeling
could be performed in very mild conditions, but this method is
restricted to metal-based tracers. We recently demonstrated that
13
conditions, i.e. 1.5 equivalent of [ C]CO generated ex situ from
11
13
17
o-iodobenzyl alcohols (o-IBA) were a versatile platform for C-
[ C]SilaCOgen in a two-chamber system, Pd(dba) (5 mol%)
2
labeling, affording the corresponding lactone after a mild and
and Xanthphos (5 mol%) in THF at 40 °C for 16h. Interestingly,
the desired lactone was produced with a good yield of 63%,
18
11
10,11,12
last-step reaction with [ C]CO (Scheme 2A).
However, to
11
our knowledge, BODIPY structures that could be labeled easily
by carbon-11 in the last-step of synthesis were still undescribed.
In this context, the design and the synthesis of novel structures
combining o-iodobenzyl alcohols and tetramethyl-BODIPY were
studied, as they could be potential precursors of bimodal tags for
PET and fluorescence imaging after conjugation to a specific
biomolecule. While aiming for a protecting-group free, safe and
reproducible synthesis, the choice of the linking strategy between
the two units would also determine the final form of the
biotracer. Indeed, a direct coupling between the two units could
which suggested a possible transfer for [ C]CO labeling.
13
Maximal absorption and emission of [ C]6 were measured at
500 nm and 516 nm, respectively, and a quantum yield of 74%
was determined in this case (see ESI for details). This
demonstrated that the photophysical properties of the
tetramethyl-BODIPY core were retained after conjugation to an
o-iodobenzyl alcohol, allowing potential applications in
fluorescence imaging. However, as the important size and
flexibility of the aryle-triazole linker could have been a drawback
for further biological studies, other methods were explored to
link directly the o-IBA unit to the meso position of the BODIPY.
13
produce a linear tracer after bioconjugation at the boron atom,
whereas tripodal compounds would be preferred in case of a
linker with a third anchoring point (Scheme 2B). In both cases,
two retrosyntheses were envisaged, i.e. direct coupling of
existing o-IBA and BODIPY moieties, or subsequent formation
of the tetramethyl-BODIPY core from an o-iodobenzyl alcohol
bearing a suitable carbonyl-based functional group (Scheme 2C).
A) Previous work
OH
O
1
1C O
I
[Pd]
Biomolecule Linker
Biomolecule Linker
O
O
11CO
RCC = 45 to 93%
RCY = 4 to 72%
Ref 12
B) This strategy
O
C
OH
I
O
O
*
C O
1) Bioconjugation
) Carbonylation
Biomolecule
2
X
N
Y
N
O
B
or
Scheme 3. Synthesis of o-iodobenzyl alcohol‒BODIPY 5 by
CuAAC and carbonylation in model conditions with [ C]CO.
N
F
N
F
N
F
N
F
B
13
B
Biomolecule
DPPA:
Diphenylphosphoryl
azide,
DBU:
1,8-
=
Bond or Linker
Y = F, O-Biomolecule
(
X = Functional group)
diazabicyclo(5.4.0)undec-7-ene, NaAsc: sodium ascorbate, dba:
dibenzylideneacetone, Xantphos: 4,5-bis(diphenylphosphino)-
C) Retrosynthetic pathways
OH
I
OH
I
9
,9-dimethylxanthene, DABCO: 1,4-diazabicyclo[2.2.2]octane.
"
BODIPY
OH
"Coupling"
synthesis"
+ 2
+ BF3
2.2. “Coupling” strategy by a Pd-catalyzed Liebeskind-Srogl
reaction
N
I
H
+
N
F
N
B
F
N
F
N
F
Z
O
B
(Z = H, OR,...)
Looking for a metal-catalyzed reaction that would be
orthogonal to the functional groups present on the o-IBA, we
Scheme 2. Last-step labeling of o-iodobenzyl alcohol
bioconjugates by [ C]CO, new o-IBA‒BODIPY tag targeted,
and retrosynthetic pathways studied.
11
firstly
considered
gold-catalyzed
couplings
between
19
aryldiazonium salts and arylboronic acids. However, this
strategy was discarded in front of the difficulties to prepare the
required starting materials, and the possibilities offered by Pd
catalysis were re-examined. In particular, the Liebeskind-Srogl
2
. Results and discussion
2
0
2
.1. “Coupling” strategy employing CuAAC
reaction is known for its characteristic neutral mechanism, and
it was previously demonstrated in the literature that methylsulfide
groups on BODIPY substrates could be selectively functionalized
with arylboronic acids partners in the presence of arylhalides and
As explained in the introductory part, our first criterion was
the design of a synthesis that would avoid any protecting group
in order to limit the overall number of steps. Thus, the coupling
reaction between the o-IBA and the BODIPY had to be tolerant
to nucleophilic benzyl alcohols and iodoaryls, which are often
reactive groups in classical nucleophilic substitutions and
palladium-catalyzed couplings. Following our previous
21
benzylalcohols. In our case, the first issue was the preparation
of a suitable o-IBA-boronic acid. Various reactions/conditions
were screened, but diazonium formation / radical borylation of 5-
19b
amino-2-iodobenzylalcohol 7 in a two-step one-pot procedure
22
1
2a,14
afforded the best results. Indeed, after optimization, the desired
experience in syntheses of bioconjugates,
copper catalyzed
15
compound 8 could be produced in 40% yield (Scheme 4).
alkyne azide cycloaddition (CuAAC) was firstly selected as

3
Having this synthon in hand, the Liebeskind-Srogl coupling with
the commercial Biellmann BODIPY 9 as model compound was
would be probably difficult, an extremely low quantum yield of
13
23
1% was measured for [ C]14, which prevented any application
performed in standard conditions, i.e. tri(2-furyl)phosphine (7.5
in fluorescent imaging. As it was probably due to oxidative
7a,27
mol%), Pd (dba)3 (2.5 mol%) and copper(I) thiophene-2-
photoinduced electron transfer (d-PeT),
the reduction of the
2
21c
carboxylate (3 equivalents) in THF at 55 °C for 1.5 h.
nitro group was investigated. Indeed, it could increase the
fluorescence quantum yield by avoiding the undesired d-PeT, and
the resulting aniline moiety could serve as anchoring point for
further bioconjugation, providing in this case tripodal PET/OI
tracers as previously depicted in Scheme 2B. Unfortunately, all
our attempts to reduce it without any side reactions with the
iodoaryl and the benzyl alcohol moieties were unsuccessful, and
this strategy was discarded.
Interestingly, the desired product 10 was obtained in 43% yield,
which demonstrated the validity of the method for unsubstituted
BODIPY. However, as no successful coupling for 1,7-
difunctionnalized BODIPY was reported in the literature
(probably due to the high increase of the steric hindrance in this
case), and the need of extra steps employing thiophosgene for the
preparation of custom Biellmann-BODIPY substrates, this
strategy was not explored any further for the targeted o-IBA‒
tetramethylated-BODIPY tags.
A) Retrosynthetic pathway
I
I
X
OH
X
O
O
O
O
N
N
B
1
F
F
B) Synthesis of o-IBA-BODIPY 13 from 1
I2 (1.8 eq),
NaIO4 (0.6 eq),
H2SO4 (98%)
KNO3 (1.2 eq),
H2SO4 (98%)
O
I
Scheme 4. Synthesis of o-iodobenzyl alcohol‒BODIPY 10 by
Liebeskind-Srogl coupling. TFP: tri(2-furyl)phosphine, dba:
dibenzylideneacetone, CuTC: copper(I) thiophene-2-carboxylate.
O
O
O2N
O2N
0°C to rt, 2h30
87%
80°C, 3 d
49%
O
O
O
1
11
12
2
.3. “BODIPY synthesis” strategy from a 4-iodophthalide
substrate
1) Et OBF4 (2 eq), DCE, 90°C (MW, 67W), 1h30
2
O N
I
3
OH
After these first investigations on the “coupling”
2)
N
(3 eq), 90°C (MW, 67W), 1h30
retrosynthetic pathway, it became clear that linking an existing
tetramethyl-BODIPY to an o-iodobenzyl alcohol moiety would
be extremely difficult without protecting the free alcohol, and/or
switching to an o-brominated version that would be less reactive
in Pd-catalyzed carbonylations. Thus, still aiming for a
protecting-group free, safe and reproducible synthesis, we
hypothesized that constructing the BODIPY core from an o-
iodobenzyl alcohol bearing a suitable carbonyl-based functional
group could be a more fruitful strategy. In a first approach, it was
decided to take advantage of the experience acquired with the
synthesis of iodobenzyl alcohol‒BODIPY 2. Indeed, using the
same reaction starting from a phthalide with an iodo-substituent
at position 4 could lead in one step to the desired o-IBA‒
tetramethylated-BODIPY compound (Scheme 5A). In this
context, phthalide 1 was firstly nitrated at its most nucleophilic
12
H
N
N
B
.
3
) Et3N (6 eq), BF3 OEt2 (9 eq),
F
F
0°C to rt, 18 h
13
0-9%
C) Pd-catalyzed carbonylation of 13 with [13C]CO
O
2
O N
I
[13
O2N
13C
C]CO (1 eq),
O
OH
Pd(dba)2 (10 mol%),
Xantphos (10 mol%),
DABCO (2 eq)
Abs = 506 nm
Em = 516 nm
= 1%
N
N
N
N
B
B
F
F
THF, 70°C, 16h
31%
F
F
[13C]14
13
Scheme 5. Synthesis of o-iodobenzyl alcohol‒BODIPY 13
and Pd-catalyzed carbonylation with [ C]CO. DCE:
dichloroethane, dba: dibenzylideneacetone, Xantphos: 4,5-
bis(diphenylphosphino)-9,9-dimethylxanthene, DABCO: 1,4-
diazabicyclo[2.2.2]octane.
13
24
position (i.e. position 6) using conditions of the literature, and
-nitrophathlide 11 could be obtained in a pure form after a
6
simple filtration with an excellent yield of 87% (Scheme 5B).
Then, looking for a method to iodinate regioselectively the
metaposition of the nitroaryl (i.e. position 4 of the phthalide),
electrophilic iodination of this highly deactivated aromatic
compound appeared as very challenging. Among the various
2.4. First “BODIPY synthesis” strategy from aldehyde 16
Subsequently, a more classical synthesis of BODIPY cores
was considered by starting from an aldehyde moiety. Indeed, the
o-IBA‒BODIPY 15 may be obtained from the corresponding
iodobenzyl alcohol 16, which could be prepared from the
commercially available synthons 17 or 18 (Scheme 6A). In the
first case, selective oxidation of one alcohol of 17 by MnO lead
to the desired product 19 with a decent yield of 46% (Scheme
B). However, when the iodination of this product was attempted
in a second step, undesired side-products resulting from the over-
oxidation of the benzylic alcohol were mainly observed, and less
than 10% of 16 could be obtained in all conditions tested (NIS,
I /AgOTf, I /NaIO /H SO ,…). Thus, it was decided to introduce
the iodine atom before the oxidation, and compound 21 was
prepared in 62% over two steps from 18 by a Sandmeyer reaction
and a consecutive double reduction of the carboxylic acids with
borane (Scheme 6C, equation 1). Then, the monooxidation of 21
25
26
conditions tested, the procedure described by Skulski et al
was the only method that afforded the desired 4-iodo-6-
nitrophthalide 12 with a satisfying yield of 49% (Scheme 5B).
Then, formation of the BODIPY core starting from this
compound was explored. Unfortunately, even after optimization
of the conditions, the desired product 13 could only be obtained
in poor and non-reproducible yields up to 9%. Despite the
unclear origin of these low yields, compound 13 was further
carbonylated in model conditions with one equivalent of
2
6
1
3
2
2
4
2
4
[
C]CO, Pd(dba) (10 mol%) and Xanthphos (10 mol%) in THF
2
13
at 70 °C for 16h, and compound [ C]14 was produced with a
modest yield of 31% after column chromatography on silica gel
(
Scheme 5C). While this result demonstrated that the
11
development of conditions for an efficient [ C]CO carbonylation
1
in 16 was investigated. As determined by H NMR analysis of

4
Tetrahedron
the crude, the di-oxidized product 23 was mainly formed for both
very good yield of 80%. Interestingly, the maximal absorption
and emission were measured at 499 nm and 510 nm, respectively,
and a fluorescence quantum yield of 48% was determined, which
demonstrated the usefulness of the targeted o-IBA‒BODIPY 15
for biological applications in fluorescence imaging. However, 16
was only obtained with a moderate yield of only 16% over three
steps, and its separation by column chromatography over silica
gel from the regioisomer 22 was too difficult to envisage the
upscaling of this method. Therefore, alternative synthetic routes
were explored to access this compound.
oxidants tested (TEMPO/BIAB and IBX) when the reaction was
1
performed in dichloromethane, with 44% and 39% H NMR ratio
for 23, respectively (Scheme 6C, entry 1 and 2). Switching to
DMSO with IBX allowed to favor the mono-oxidized products
1
1
6 and 22 (sum of 52% H NMR ratio, Scheme 6C, entry 3).
Unfortunately, the steric hindrance originating from the iodine
atom was not sufficient to induce high levels of regioselectivity,
1
as the 16/22 ratio observed by H NMR was roughly 2/1, and the
desired product 16 could only be obtained with an isolated yield
of 26% in this case.
A) Retrosynthetic pathway
OH
I
OH
I
OH
OH
O
OH
NH2
or
N
N
B
O
H
HO
O
F
F
1
5
16
17
18
B) Attempted synthesis of synthon 16 from 17
OH
H
OH
OH
+
Mn.O2 (1.5 eq)
CH2Cl2, reflux, 48h
"
I "
I
Iodination
<
10%
4
6%
OH
O
O
H
1
7
19
16
C) Synthesis of synthon 16 from 18
Scheme 7. Synthesis of o-iodobenzyl alcohol‒BODIPY 15
and its Pd-catalyzed carbonylation with [ C]CO. DDQ: 2,3-
dichloro-5,6-dicyano-p-benzoquinone, dba: dibenzylidene-
acetone, Xantphos: 4,5-bis(diphenylphosphino)-9,9-dimethyl-
xanthene, DABCO: 1,4-diazabicyclo[2.2.2]octane.
13
1
2
) NaNO2 (2.5 eq),
H2O/HCl(37%),
0°C, 30 min
O
OH
NH2
O
OH
I
OH
I
BH3.THF (4.8 eq)
THF, rt, 16h
(
1)
) KI (6 eq), rt, 19h
62%
HO
O
HO
O
OH
1
00%
2
.5. Optimized synthesis of aldehyde 16 for the “BODIPY
1
8
20
21
synthesis” strategy
OH
I
H
O
H
O
O
In particular, as the esterification of 18 in 25 (Scheme 8A)
I
I
28
Oxidation
+
+
+
21
was previously described in the literature, we hypothesized that
selective reduction steps may be performed from this compound
to install the alcohol and aldehyde moieties at the desired
positions. In a first attempt, the Sandmeyer reaction was realized
at the beginning of the sequence to produce the desired iodoaryl
26 with a good yield of 70%. However, in this case, the first
(
2)
21
O
H
OH
22
H
1
6
23
6/22/23/21 1H NMR ratio
1
Oxidant
Entry
Solvent
Conditions
(x eq)
(isolated yield of 16)
reduction of the carboxylic acid using a combination of
TEMPO (0.1 eq)
BIAB (1 eq)
1
2
3
CH2Cl2
CH2Cl2
DMSO
rt, 18h
reflux,
9/17/44/30 (n.i.)
23/19/39/19 (n.i.)
33/19/24/24 (26%)
29
NaBH /I2 only led to small amounts of desired 27 (19% isolated
4
IBX (1 eq)
IBX (1 eq)
yield) among various deiodinated side-products. On the contrary,
2
2h
performing the reduction directly from 25 using the NaBH /I
4
2
rt, 30 min
method led to the expected benzyl alcohol 28 with a very good
yield of 81%. Moreover, its iodination by a Sandmeyer reaction
using the previous conditions afforded 27 with a very good yield
of 87%. Then, the controlled reduction of the ester moiety of 27
in aldehyde was explored, and the best result (75% yield of 16)
was obtained by a one-pot amidation with freshly prepared
diisobutylaluminum morpholide, and consecutive reduction by
Scheme 6. Retrosynthetic pathways envisaged for the o-
iodobenzyl alcohol 16, first attempt from 17 and synthesis of 16
from 18. TEMPO: 2,2,6,6-tetramethylpiperidine 1-oxyl, BAIB:
diacetoxyiodo)benzene, IBX: 2-iodoxybenzoic acid, n.i.: non
isolated.
(
3
0
diisobutylaluminum hydride.
This optimized sequence
However, with compound 16 in hand, we decided to evaluate
delivered 16 in only four steps from the commercial and
inexpensive 18 with an overall yield of 46%. This was almost
three times the value obtained with the previous strategy
described in part 2.4, and this four-steps sequence was selected as
the optimal method to give BODIPY 15 with the best
compromise between yield, length, safety and reproducibility.
the next steps of the synthesis, i.e. the “BODIPY formation” and
the carbonylation of the resulting structure. Thus, 16 was
engaged with 2,4-dimethylpyrrole under acidic conditions, the
resulting intermediate was oxidized by DDQ and reacted with
boron trifluoride etherate under basic conditions to produce the
desired BODIPY 15 with a good yield of 65% (Scheme 7A).
13
Furthermore, this compound could react smoothly with [ C]CO
in THF at 70 °C for 1h in presence of the Pd(dba) /Xanthphos
2
13
catalytic system, affording the desired product [ C]24 with a

5
benzoquinone, dba: dibenzylidene-acetone, Xantphos: 4,5-
bis(diphenylphosphino)-9,9-dimethyl-xanthene, DABCO: 1,4-
diazabicyclo[2.2.2]octane.
3
. Conclusion
To conclude, various syntheses of iodobenzyl alcohol‒
BODIPY structures were designed and performed, aiming
potential precursors of bimodal tags for positron emission
tomography and optical imaging. After demonstrating that the
photophysical properties of the tetramethyl-BODIPY core were
retained after their linking to an o-iodobenzyl alcohol by
CuAAC, new methods to obtain “fused” compounds were
explored. Firstly,
a Liebeskind-Srogl coupling could be
performed using the suitable boronic acid 8 with the Biellmann
BODIPY 9, but this strategy was discarded for the synthesis of
the targeted tetramethylated BODIPY. Then, the subsequent
formation of the BODIPY core was investigated from an o-
iodobenzyl alcohol bearing a suitable carbonyl-based functional
group. Employing the 4-iodo-6-nitrophthalide 12 lead to the
desired o-IBA‒BODIPY 13 in poor and non-reproducible yields,
1
3
whereas the corresponding carbonylated product [ C]14
exhibited an extremely low quantum yield of 1%, which
prevented any application in fluorescent imaging. Finally, the
promising o-IBA‒BODIPY structure 15 (possessing both a good
fluorescence quantum yield and an excellent reactivity in Pd-
catalyzed alkoxycarbonylation) could be obtained with a good
yield of 65% from intermediate 16. Whereas this latter one was
firstly produced in 16% yield from 18 by a three-step protocol of
iodination/reduction in alcohols/oxidation in aldehyde, a slightly
longer sequence, i.e. selective methylation / reduction in alcohol /
iodination / reduction in aldehyde, was more practical and
efficient (46% over 4 steps). Conjugation of the resulting
Scheme 8. Alternative pathways for the synthesis of o-
iodobenzyl alcohol 16. TMSCl: trimethylsilyl chloride, p-TsOH:
p-toluenesulfonic acid, DIBAL-H: diisobutylaluminum hydride.
To summarize, the overall procedure for synthesizing the o-
IBA‒tetramethylated-BODIPY 15 and its corresponding lactone
13
tag [ C]24 are described in Scheme 9. Further bioconjugation of
13
these structures are currently under investigation in order to
provide new PET/fluorescence imaging bimodal tracers.
13
precursor 15 and tag [ C]24 to various molecules of biological
13
interest are currently under investigation, and these results will
be disclosed in further studies along with the in vitro / in vivo
evaluations of the resulting bioconjugates.
4
. Experimental section
All commercial materials 1 were used without further
13
purification, unless indicated. H NMR and C NMR were
1
recorded on a BRUKER AVANCE I 300 MHz spectrometer ( H:
1
3
3
00MHz, C: 75.3MHz) and a BRUKER AVANCE III 600
1 13
MHz spectrometer ( H: 600MHz, C: 150.3MHz). The chemical
shifts for the NMR spectra are reported in ppm relative to the
solvent residual peak. Coupling constants J are reported in hertz
(Hz). The following abbreviations are used for the multiplicities:
s, singlet; d, doublet; t, triplet; q, quartet; qt, quintet; st, sextet; m,
multiplet; br, broad; dd, doublet of doublet. Yields refer to
isolated material determined to be pure by NMR spectroscopy
and thin-layer chromatography (TLC), unless specified in the
text. Analytical TLC was performed on Fluka Silica Gel 60 F254.
High resolution mass spectra were performed by the CESAMO
(
Talence, France) and were recorded on Q-TOF tandem mass
spectrometer (API Q-STAR Pulsari, Applied Biosystems).
Positive ion mode ESI-MS was used for the analyses. The two-
chamber
system
was
bought
at
SyTracks
(http://www.sytracks.com).
4
4
.1. 8-(2-Hydroxymethylphenyl)-1,3,5,7-tetramethyl-4,4-difluoro-
-bora-3a,4a-diaza-s-indacene (2)
Scheme 9. Summary of the1 synthesis of o-IBA‒
3
tetramethylated-BODIPY
16,
C-carbonylation,
and
To a solution of phthalide 1 (1 eq, 0.750 mmol, 100 mg) in
11
bioconjugation envisaged to obtain precursors for C-labeling
for PET and fluorescence imaging tracers. TMSCl: trimethylsilyl
0.75 mL of anhydrous dichloromethane under N was added a
2
solution of triethyloxonium tetrafluoroborate (5M in
dichloromethane, 2 eq, 1.5 mmol, 0.30 mL). The resulting
solution was stirred under reflux for 24h. After cooling down to 0
chloride,
p-TsOH:
paratoluensulfonic
acid,
DIBAL:
diisobutylaluminum,
DDQ: 2,3-dichloro-5,6-dicyano-p-

6
Tetrahedron
+
°
C, 2,4-dimethylpyrrole (3 eq, 2.25 mmol, 0.230 mL) was added
(ESI/TOF+): C H BF IN O [M+Na] calculated 704.1475,
31
31
2
5
2
-
1
and the resulting mixture was stirred under reflux for 4h. After
cooling down to 0 °C, triethylamine (6 eq, 4.5 mmol, 0.63 mL)
and borontrifluoride diethyl etherate complex (9 eq, 6.75 mmol,
found 704.1485; νmax/cm : 3336 (O-H), 2925 (=C-H ), 1546
Ar
(C=C ), 1193 (C-N), 1156 (C-O).
Ar
13
4
.4. [ C]-5-((1-(2-(5,5-Difluoro-1,3,7,9-tetramethyl-5H-4l4,5l4-
dipyrrolo[1,2-c:2',1'-f][1,3,2]-diaza-borinin-10-yl)benzyl)-1H-
,123,3-triazol-4-yl)methoxy)-6-methylisobenzofuran-1(3H)-one
1
.80 mL) were added dropwise, and the reaction mixture was
stirred at rt for 2h. The reaction mixture was diluted with
dichloromethane and washed three times with water and with a
saturated aqueous solution of sodium chloride. The organic layer
was dried over Na SO and concentrated under reduced pressure.
Then, in order to remove the unreacted phthalide 1, the residue
was stirred in a mixture of dichloromethane and an aqueous
solution of NaOH (1M) at room temperature overnight. The
organic layer was separated, washed with water and with a
saturated aqueous solution of sodium chloride, dried over
anhydrous Na SO and concentrated under reduced pressure. The
1
([ C]6)
2
4
In the chamber 1 of the two-chamber system was added
Ph MeSi COOH (8.2 mg, 0.13 mmol, 1.5 eq.). The chamber 1
was sealed with a screwcap fitted with a silicone/PTFE seal. In
the chamber 2 of the two-chamber system were added
successively o-IBA-BODIPY 5 (23.3 mg, 34.0 µmol, 1.0 eq.),
13
2
Pd(dba) (1.0 mg, 1.7 µmol, 0.05 eq.), Xantphos (1.0 mg, 1.7
µmol, 0.05 eq.) and DABCO (7.6 mg, 68 µmol, 2.0 eq.). The
2
2
4
residue was purified by silica gel column chromatography
petroleum ether/ethyl acetate : 8/2) to give the desired BODIPY
(104 mg, 40%) as orange crystals; R (cyclohexane/ethyl
chamber 2 was sealed with a screwcap fitted with a
(
2
silicone/PTFE seal. The atmosphere of the two-chamber system
was purged three times with argon. Then, 1 mL of dry THF was
added by syringe in each chamber through the silicone/PTFE
seal. The loaded two-chamber system was stirred at 40 °C, then a
solution of TBAF (5 µL, 1M in THF, 5 µmol, 15 mol%) was
added through the silicone/PTFE seal in the chamber 1. The
system was stirred at 40 °C for 16 hours. After a careful opening,
the crude reaction mixture from chamber 2 was concentrated
under reduced pressure. The residue was purified by silica gel
f
1
acetate/: 8/2) 0.17; H NMR (300 MHz CDCl ) δ (ppm): 7.65
3
(
1
=
6
dd, J = 6.3 Hz, J = 1.3 Hz, 1H), 7.52 (td, J = 7.6 Hz, J = 1.5 Hz,
H), 7.42 (td, J = 7.5 Hz, J = 1.3 Hz, 1H), 7.20 (dd, J = 7.6 Hz, J
1.5 Hz, 1H), 5.98 (s, 2H), 4.60 (s, 2H), 2.56 (s, 6H), 1.36 (s,
16
H). The spectral data was in accordance with the literature.
4
4
.2. 8-(2-(Azidomethyl)phenyl)-1,3,5,7-tetramethyl-4,4-difluoro-
-bora-3a,4a-diaza-s-indacene (3)
flash chromatography (cyclohexane/ethyl acetate
:
50/50)
13
To a solution of BODIPY 2 (1 eq, 0.970 mmol, 343 mg) and
DBU (1.30 eq, 1.26 mmol, 0.19 mL) in 30 mL of distilled
toluene under nitrogen was added DPPA (1.20 eq, 1.16 mmol,
affording product [ C]6 (40.2 mg, 63%) as a white powder; mp :
1
195 °C; R
MHz, CDCl
(cyclohexane/ethyl acetate : 50/50) 0.2; H NMR (300
) δ (ppm): 7.65 (d, J = 2.0 Hz, 1H), 7.55-7.50 (m,
f
3
0
.25 mL). The resulting solution was stirred at 60 °C for 3h. The
reaction mixture was quenched with an aqueous solution of HCl
1M). The aqueous layer was extracted four times with EtOAc,
3H), 7.30-7.27 (m, 1H), 7.01 (s, 1H), 5.94 (s, 2H), 5.40 (s, 2H),
5.20 (d, J = 2.0 Hz, 1H), 5.16 (s, 2H), 2.56 (s, 6H), 2.24 (s, 3H),
13
13
(
1.22 (s, 6H); C NMR (150.6 MHz, CDCl ) δ (ppm): 171.3 ( C-
3
the combined organic layers were washed once with water and
once with a saturated aqueous solution of NaCl, dried over
anhydrous Na SO and concentrated under reduced pressure. The
enriched), 161.7, 156.6, 147.4, 143.1, 138.2, 134.1, 132.3, 130.9,
130.8, 130.3, 129.9, 129.4, 129.0, 127.3, 124.1, 121.8, 118.2,
117.7, 104.0, 69.3, 62.2, 51.8, 32.1, 29.9, 29.5, 29.3, 22.8, 16.9,
+
2
4
13
residue was purified by silica gel column chromatography
14.8, 14.0, 1.2; HRMS (ESI/TOF+): C31 CH30BF N O [M+Na]
2 5 3
-1
(cyclohexane/ethyl acetate : 90/10) to give the azido-BODIPY 3
calculated 605.2339, found 605.2355; νmax/cm : 2927 (=C-HAr),
1710 (C=O), 1545 (C=CAr), 1194 (C-N), 1157 (C-O).
(
9
2
265 mg, 72%) as a red solid; R (cyclohexane/ethyl acetate :
f
1
0/10) 0.29. H NMR (300 MHz CDCl ) δ (ppm): 7.59-7.50 (m,
3
4
.5. (3-(Hydroxymethyl)-4-iodophenyl)boronic acid (8)
H), 7.46 (dt, J = 7.2, J = 1.7 Hz, 1H), 7.42-7.33 (m, 1H), 6.00
(
s, 2H), 4.34 (s, 2H), 2.57 (s, 6H), 1.35 (s, 6H). The spectral data
HBF (48% aqueous solution, 2.5 eq, 15 mmol, 1.96 mL) was
4
16
18b
was in accordance with the literature.
added to a suspension of (5-amino-2-iodophenyl)methanol 7 (1
eq, 6.00 mmol, 1.49 g) in 7.5 mL of water at room temperature
and the reaction mixture was stirred for 1 min before being
4
.3. (5-((1-(2-(5,5-Difluoro-1,3,7,9-tetramethyl-5H-4l4,5l4-
dipyrrolo[1,2-c:2',1'-f][1,3,2]diazaborinin-10-yl)benzyl)-1H-
cooled to 0 °C. A solution of NaNO (1.2 eq, 7.20 mmol, 497
2
1
,2,3-triazol-4-yl)methoxy)-2-iodo-4-methylphenyl)methanol (5)
Under inert atmosphere, azido-BODIPY 3 (1 eq, 0.24 mmol,
mg) in 3.7 mL of water was added dropwise with a syringe, and
the reaction mixture was stirred for 15 min at 0 °C. The solution
was then added dropwise to an aqueous solution at 0 °C (45 mL)
of B (OH) (2 eq, 12.0 mmol, 1.04 g) and NaHCO (2 eq, 12.0
9
1 mg) was dissolved in 4 mL of tBuOH/H O (3/1). (2-Iodo-4-
2
12a
methyl-5-(prop-2-yn-1-yloxy)phenyl)methanol 4 (1.1 eq, 0.26
mmol, 79 mg), pentahydrate copper sulphate (0.1 eq, 24 μmol,
6
then added successively. The mixture was stirred at 40 °C for 16
hours. The crude reaction mixture was concentrated under
reduced pressure. The residue was purified by silica gel flash
chromatography (cyclohexane/ethyl acetate : gradient 90/10 then
2
4
3
mmol, 1.01 g). Then, the mixture was stirred at room temperature
for 15 min. Ethyl acetate (30 mL) and HCl (6M aqueous
solution) were added to the reaction mixture until reaching pH =
6, and the aqueous layer was extracted two times with ethyl
acetate. Then, the combined organic layers were concentrated to
30 mL and were transferred into a separatory funnel. 30 mL of an
aqueous solution of sorbitol (1M) and 30 mL of an aqueous
solution of Na CO (1M) were added. The two layers were hand
.0 mg) and sodium ascorbate (1 eq, 0.24 mmol, 48 mg) were
5
0/50) to give the o-IBA-BODIPY 5 (120 mg, 73%) as an orange
powder; mp : 128 °C; R (cyclohexane/ethyl acetate : 50/50) 0.3;
f
2
3
1
H NMR (300 MHz CDCl ) δ (ppm): 7.53-7.51 (m, 4H), 7.29-
shaken in the separatory funnel for about 5 min, and the organic
layer was discarded. The aqueous layer was placed in a flask
equipped with a suitable size stir-bar, and cooled in an ice-water
cooling bath. An HCl aqueous solution (6M) was added slowly
until reaching pH 2-3. The solution was transferred into an
appropriate separatory funnel, an equal amount of ethyl acetate
was added and the aqueous layer was extracted three times. The
3
7
2
.26 (m, 1H), 7.24 (s, 1H), 7.08 (s, 1H), 5.95 (s, 2H), 5.39 (s,
H), 5.08 (s, 2H), 4.60 (s, 2H), 2.61 (br s, 1H), 2.55 (s, 6H), 2.12
13
(s, 3H), 1.23 (s, 6H); C NMR (75.3 MHz, CDCl ) δ (ppm):
3
1
1
1
57.0, 156.7, 143.7, 143.1, 141.4, 140.6, 138.2, 135.0, 134.0,
32.5, 130.9, 130.6, 130.3, 129.8, 128.9, 128.8, 123.9, 121.8,
12.0, 86.1, 77.4, 69.2, 61.9, 51.6, 41.1, 15.7, 14.8, 14.0; HRMS

7
combined organic layers were washed twice with water, dried
with anhydrous MgSO4 and filtered. The residue was
concentrated to give the desired (3-(hydroxymethyl)-4-
4.9. 5,5-Difluoro-10-(2-(hydroxymethyl)-3-iodo-5-nitrophenyl)-
1,3,7,9-tetramethyl-5H-dipyrrolo[1,2-c:2',1'-
f][1,3,2]diazaborinin-4-ium-5-uide (13)
1
iodophenyl)boronic acid 8 (664 mg, 40%) as a brown solid; H
Under nitrogen atmosphere, to a solution of 4-iodo-6-
nitroisobenzofuran-1(3H)-one 12 (1 eq, 0.16 mmol, 51 mg) in 0.4
mL of distilled dichloroethane in a sealed tube was added
Et OBF (5M in dichloromethane) (2 eq, 0.32 mmol, 66 μL). The
NMR (300 MHz, DMSO-d ) δ (ppm): 6.8 (s, 1H), 6.7 (d, J = 7.8
6
Hz, 1H), 6.31 (dd, J = 1.9, 7.8 Hz, 1H), 4.4 (t, J = 5.6 Hz, 1H),
3
.34 (d, J = 5.5 Hz, 2H).
3
4
4
.6. (5-(5,5-Difluoro-5H-4l4,5l4-dipyrrolo[1,2-c:2',1'-
resulting solution was stirred under micro-wave irradiation at 90
°C for 1h30. Then 2,4-dimethylpyrrole (3 eq, 0.49 mmol, 51 μL)
was added at rt. The reaction mixture was stirred under micro-
wave irradiation at 90 °C for 1h30. Then triethylamine (6 eq,
f][1,3,2]diazaborinin-10-yl)-2-iodophenyl)methanol (10)
A Schlenk tube equipped with a stir bar was charged with
Beillman BODIPY 9 (1 eq, 0.38 mmol, 90 mg), the (3-
0
0
.98 mmol, 0.14 mL) and BF ·OEt (45% w/w) (9 eq, 1.5 mmol,
.40 mL) were added dropwise at 0 °C. The resulting solution
3 2
(hydroxymethyl)-4-iodophenyl)boronic acid 8 (3 eq, 1.14 mmol,
3
16 mg), and dry THF (15 mL). The mixture was purged with N2
was stirred at room temperature for 18h and diluted with
dichloromethane, washed three times with distilled water and
once with brine, dried over anhydrous Na SO and concentrated
for 5 min, and Pd (dba)3 (0.03 eq, 11 μmol, 10 mg),
trifurylphosphine (0.07 eq, 26 μmol, 6.0 mg), and CuTC (3 eq,
1
then immersed in a preheated oil bath at 55 °C. The oil bath was
removed after the starting BODIPY was consumed (3h) (checked
by TLC, cyclohexane/ethyl acetate : 80/20). After the mixture
reached room temperature, the crude material was adsorbed on
silica gel, and the product was purified by silica gel flash
chromatography (cyclohexane/ethyl acetate : 80/20) to give the
2
2
4
.14 mmol, 217 mg) were added under N . The Schlenk tube was
2
under reduced pressure. The residue was dissolved in
dichloromethane and stirred in the presence of an aqueous
solution of sodium hydroxide (1M) at room temperature for 16h.
After separation, the resulting organic layer was washed with
distilled water and brine, dried over anhydrous Na SO and
2
4
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (petroleum ether/ethyl acetate :
desired compound 10 (68 mg, 43 %) as a red-green-yellow solid;
8
/2) to give the desired compound 13 (8 mg, 9%) as an orange
1
H NMR (300 MHz, CDCl ) δ (ppm): 7.97 (d, J = 8.0 Hz, 1H),
1
3
solid; R (petroleum ether/ethyl acetate : 8/2) 0.22; H NMR (300
f
7
.93 (s, 2H), 7,67 (s, 1H), 7.18 (dd, J = 1.7, J =8.0 Hz, 1H), 6.9
MHz, CDCl ) δ (ppm): 8.84 (d, J = 2.3 Hz, 1H), 8.16 (d, J = 2.3
3
(d, J = 3.9 Hz, 2H), 6.53 (d, J =3.1 Hz, 2H), 4.76 (s, 2H).
Hz, 1H), 6.04 (s, 2H), 4.76 (d, J = 6.0 Hz, 2H), 2.57 (s, 6H), 1.38
13
4
.7. 6-Nitroisobenzofuran-1(3H)-one (11)
(s, 6H); C NMR (75.3 MHz, CDCl
3
) δ (ppm): 157.5, 147.9,
1
46.9, 142.6, 137.0, 135.5, 130.8, 124.0, 122.4, 101.0, 65.6, 15.0;
+
A solution of phthalide 1 (1 eq, 22 mmol, 3.0 g) in 30 mL of
HRMS (TOF MS): C H BN O F NaI [M+Na] , calculated
20
19
3
3 2
H SO (95-98%) was added dropwise at 0°C to a solution of
KNO (1.2 eq, 26.0 mmol, 2.63 g) in 12 mL of H SO (95-98%).
2
4
548.0424, found 548.0423.
3
2
4
1
3
4
1
.10. [ C]-5,5-Difluoro-1,3,7,9-tetramethyl-10-(6-nitro-1-oxo-
,3-dihydroisobenzofuran-4-yl)-5H-dipyrrolo[1,2-c:2',1'-
The reaction mixture was stirred at room temperature for 2h30
and then poured on ice. The resulting precipitate was filtered
under reduced pressure and washed with distilled water. The
filtrate was once again filtered under reduced pressure and the
remaining solid was washed with distilled water. The combined
solids were dried under reduced pressure to give 6-
13
f][1,3,2]diazaborinin-4-ium-5-uide ([ C]14)
In the chamber 1 of the two-chamber system was added
13
Ph MeSi COOH (0.9 eq, 5.0 mg, 23 μmol). The chamber 1 was
2
sealed with a screwcap fitted with a silicone/PTFE seal. In the
chamber 2 of the two-chamber system was added compound 13
nitroisobenzofuran-1(3H)-one 11 (3.41 g, 87%) as an off-white
solid; R (petroleum ether/ethyl acetate : 70/30) 0.19; H NMR
1
f
(
1 eq, 13 mg, 25 μmol), Pd(dba) (0.1 eq, 3 μmol, 1 mg),
2
(300 MHz, CDCl ) δ (ppm): 8.78 (d, J = 2.1, 0.7 Hz, 1H), 8.58
3
Xantphos (0.1 eq, 2 μmol, 1 mg) and DABCO (2 eq, 50 μmol,
.0 mg). The chamber 2 was sealed with a screwcap fitted with a
(dd, J = 8.4, J = 2.1 Hz, 1H), 7.72 (dd, J = 8.4, J = 0.7 Hz, 1H),
6
+
5
2
.45 (s, 2H); HRMS (ESI): C H O N [M+Na] , calculated
8
5
4
silicone/PTFE seal. The atmosphere of the two-chamber system
was purged three times with nitrogen. Then, 1 ml of anhydrous
THF was added by syringe in each chamber through the
silicone/PTFE seal. The loaded two-chamber system was stirred
at 70 °C, then 5 µL of a solution of TBAF (1M in THF, 5 µmol,
20 mol%) were added through a silicone/PTFE seal in the
chamber 1. The system was stirred at 70 °C for 16 hours. After a
careful opening, the crude reaction mixture from chamber 2 was
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (petroleum ether/diethyl ether :
02.0111, found 202.0105. The spectral data was in accordance
24
with the literature.
4
.8. 4-Iodo-6-nitroisobenzofuran-1(3H)-one (12)
Iodine (1.8 eq, 20.2 mmol, 5.13 g) was added to 34 mL of
H SO (95-98%) followed by NaIO (0.6 eq, 6.70 mmol, 1.43 g).
2
4
4
The resulting mixture was stirred at 30°C for 30 min, then 6-
nitroisobenzofuran-1(3H)-one 11 (1 eq, 11.2 mmol, 2.00 g) was
added. The reaction mixture was stirred at 80 °C for 3 days, then
poured on ice. The resulting precipitate was filtered under
reduced pressure. The solid was dissolved in dichloromethane,
washed with an aqueous solution of sodium thiosulfate (10%)
and distilled water. The organic layer was dried over anhydrous
Na SO and concentrated under reduced pressure to give 4-iodo-
13
70/30) to give the desired compound [ C]14 (3 mg, 31%) as an
orange solid; mp : 225 °C; R (petroleum ether/diethyl ether :
f
1
70/30) 0.25; H NMR (300 MHz, CDCl ) δ (ppm): 8.88 (dd, J =
3
3.1, J = 2.0 Hz, 1H), 8.54 (d, J = 2.0 Hz, 1H), 6.07 (s, 2H), 5.25
1
3
2
4
(d, J = 2.1 Hz, 2H), 2.59 (s, 6H), 1.68 (s, 2H), 1.34 (s, 6H);
C
13
6
-nitroisobenzofuran-1(3H)-one 12 (1.66 g, 49%) as a white
NMR (150.3 MHz, CDCl ) δ (ppm): 167.6 ( C-enriched), 158.5,
3
solid; mp : 157 °C; R (cyclohexane/ethyl acetate : 70/30) 0.38;
150.9, 141.5, 129.1, 122.9, 122.1, 69.2, 53.6, 29.9, 29.5, 28.1,
f
1
13
-
H NMR (300 MHz, CDCl ) δ (ppm): 8.89 (d, J = 1.9 Hz, 1H),
22.9, 15.0, 14.8; HRMS (ESI): C20 CH BF N O [M-H]
3
18
-1
2
3
4
13
8
.73 (d, J = 1.9 Hz, 1H), 5.20 (s, 2H); C NMR (75.3 MHz,
calculated 424.1356, found 424.1348; νmax/cm : 3030 (=C-H ),
Ar
CDCl ) δ (ppm): 168.1, 156.5, 137.5, 128.9, 121.0, 88.6, 72.8,
1
3
1733 (C=O), 1545 (C-NO ), 1346 (C-NO ), 1060 (C-O).
3
2
2
+
.2; HRMS (TOF MS): C H O NNaI [M+Na] , calculated
8 4 4
-1
4.11. 5,5-Difluoro-10-(4-(hydroxymethyl)-3-iodophenyl)-1,3,7,9-
tetramethyl-5H-dipyrrolo[1,2-c:2',1'-f][1,3,2]diazaborinin-4-
ium-5-uide (15)
27.9077, found 327.9082; νmax/cm : 3087 (=C-H ), 1770
Ar
(C=O), 1534 (C-NO ), 1345 (C-NO ), 1090 (C-O).
2
2

8
Tetrahedron
1
Under nitrogen atmosphere, to
a
solution of 4-
40/60) 0.44; H NMR (300 MHz, CDCl ) δ (ppm) : 10.00 (s, 1H),
3
(
hydroxymethyl)-3-iodobenzaldehyde 16 (1 eq, 2.26 mmol, 591
7.87 (d, J = 8.2 Hz, 2H), 7.53 (d, J = 8.2 Hz, 2H), 4.80 (s, 2H).
3
1
mg) and 2,4-dimethylpyrrole (2.2 eq, 4.94 mmol, 591 ꢀL) in 30
mL of anhydrous THF was added trifluoroacetic acid (0.4 eq,
0
temperature overnight. A solution of DDQ (1 eq, 2.26 mmol, 513
mg) in 30 mL of anhydrous THF was added and the resulting
mixture was stirred for five hours. At 0 °C were added
The spectral data was in accordance with the literature.
.14. 2-Iodoterephthalic acid (20)
To a suspension of 2-aminoterephthalic acid 18 (1 eq, 5.5
4
.90 mmol, 69 ꢀL). The resulting mixture was stirred at room
mmol, 1.0 g) in 30 mL of distilled H O/ concentrated aqueous
2
solution of HCl :1 / 1 was added dropwise a solution of sodium
nitrite (2.5 eq, 13.8 mmol, 952 mg) in 10 mL of distilled water at
triethylamine (11.5 eq, 26.0 mmol, 3.60 mL) and BF .OEt (16
3
2
eq, 36 mmol, 4.5 mL) dropwise. The resulting solution was
stirred overnight at room temperature, and then washed two times
with distilled water. The aqueous layers were extracted twice
with ethyl acetate, and the combined organic layers were dried
0
°C. The resulting solution was stirred at 0 °C for 30 min. The
reaction mixture was poured into a solution of potassium iodide
6 eq, 33 mmol, 5.5 g) in 50 mL of distilled water. The resulting
(
dark solution was stirred at room temperature for 19h. Sodium
thiosulfate was added until the solution became light brown. The
resulting solid was filtered under vacuum, triturated with a
biphasic mixture of dichloromethane/H O :50/50, and dried
under vacuum to give the 2-iodoterephthalic acid 20 (1.6 g,
quant.) as a tan coloured solid; R (ethyl acetate/petroleum
ether/acetic acid : 40/60/1) 0.19; H NMR (300 MHz, Acetone-
d6) δ (ppm): 8.61 (d, J = 1.6 Hz, 1H), 8.13 (dd, J = 8.0, J =1.6
Hz, 1H), 7.94 (d, J = 8.0 Hz, 1H). The spectral data was in
over anhydrous Na SO and concentrated under reduced pressure.
2
4
The residue was purified by silica gel column chromatography
pentane/ethyl acetate : 80/20 then 70/30 then 60/40 then 50/50)
to give the BODIPY (707 mg, 65%) as an orange solid; mp : 230
(
2
1
°
C; R (ethyl acetate/petroleum ether : 30/70) 0.47; H NMR (300
f
f
1
MHz, CDCl ) δ (ppm): 7.78 (d, J = 1.6 Hz, 1H), 7.61 (d, J = 7.8
3
Hz, 1H), 7.33 (dd, J = 7.8, J = 1.6 Hz, 1H), 5.99 (s, 2H), 4.76 (s,
13
2
H), 2.55 (s, 6H), 1.43 (s, 6H) ; C NMR (75.3 MHz, CDCl ) δ
3
32
(ppm): 156.1, 143.8, 143.1, 139.3, 138.5, 136.1, 131.4, 128.5,
accordance with the literature.
.15. (2-Iodo-1,4-phenylene)dimethanol (21)
Under nitrogen atmosphere, to
1
28.4, 121.6, 96.9, 69.1, 29.9, 15.0, 14.8 ; HRMS (ESI):
10
127
+
4
C H ON BF2
4
1
I
[M+H]
calculated 480.0790, found
20
20
2
-
1
80.0790; νmax/cm : 3534 (O-H), 2924 (=C-H ), 1546 (C=C ),
Ar
Ar
a
suspension of 2-
193 (C-O), 1157 (C-N).
.12. 4-(Hydroxymethyl)-3-iodobenzaldehyde (16)
Under a nitrogen atmosphere, to a solution of morpholine (3.1
iodoterephthalic acid 20 (1 eq, 0.340 mmol, 100 mg)) in 2 mL of
anhydrous THF was added a solution of BH ·THF in THF (1M)
4.8 eq, 1.6 mmol, 1.6 mL) dropwise. The resulting mixture was
4
3
(
stirred at room temperature for 16h and quenched with distilled
water and an aqueous solution of HCl (1M). The aqueous layer
was extracted three times with ethyl acetate. The combined
organic layers were dried over anhydrous Na SO and
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (cyclohexane/EtOAc : 60/40)
to afford the (2-iodo-1,4-phenylene)dimethanol 21 (56 mg, 62%)
eq, 0.62 mmol, 55 ꢀL) in 2 mL of anhydrous THF was added
DIBAL-H (3 eq, 0.60 mmol, 0.60 mL) dropwise at 0 °C. The
resulting mixture was stirred at 0 °C for 3h and poured on the
methyl 4-(hydroxymethyl)-3-iodobenzoate 27 (1 eq, 0.20 mmol,
2
4
5
8 mg) under nitrogen atmosphere. The reaction mixture was
stirred at reflux overnight. To the reaction mixture was added
DIBAL-H (2 eq, 0.40 mmol, 0.40 mL) dropwise at room
temperature. The resulting mixture was stirred at reflux for 6h.
After returning to room temperature, the reaction mixture was
quenched with an aqueous solution of HCl (1M), the aqueous
as a white solid; R (ethyl acetate/petroleum ether : 40/60) 0.23;
f
1
H NMR (300 MHz, DMSO-d ) δ (ppm) : 7.75 (s, 1H), 7.41 (d, J
6
=
7.6 Hz, 1H), 7.33 (d, J = 7.6 Hz, 1H), 5.39 (t, J = 5.5 Hz, 1H),
.24 (t, J = 5.8 Hz, 1H), 4.45 (d, J = 5.8 Hz, 2H), 4.39 (d, J = 5.5
Hz, 2H). The spectral data was in accordance with the
5
layer was extracted three times with Et O. The combined organic
2
33
layers were dried over anhydrous Na SO and concentrated under
2
4
literature.
reduced pressure. The residue was purified by silica gel column
chromatography (petroleum ether/ethyl acetate : 80/20) to give
the 4-(hydroxymethyl)-3-iodobenzaldehyde (39 mg, 75%) as a
4
.16. 5,5-Difluoro-1,3,7,9-tetramethyl-10-(3-oxo-1,3-
dihydroisobenzofuran-5-yl)-5H-dipyrrolo[1,2-c:2',1'-
f][1,3,2]diazaborinin-4-ium-5-uide ([ C]24)
13
white solid; mp : 86 °C; R (petroleum ether/ethyl acetate : 70/30)
f
1
0
.38; H NMR (300 MHz, CDCl ) δ (ppm): 9.94 (s, 1H), 8.31 (d,
3
In the chamber 1 of the two-chamber system was added
J = 1.6 Hz, 1H), 7.89 (dd, J = 7.9, 1.6 Hz, 1H), 7.69 (d, J = 7.9
13
Ph MeSi COOH (0.9 eq, 40 ꢀmol, 10 mg). The chamber 1 was
sealed with a screwcap fitted with a silicone/PTFE seal. In the
chamber 2 of the two-chamber system was added compound 15
13
2
Hz, 1H), 4.74 (s, 2H); C NMR (75.3 MHz, CDCl ) δ (ppm):
3
1
90.5, 149.2, 140.1, 137.0, 129.9, 128.3, 96.9, 69.2; HRMS
127 -
(ESI): C H O I [M-H] , calculated 260.9418, found 260.9412;
8 7 2
-1
(1 eq, 44 ꢀmol, 21 mg), Pd(dba) (0.1 eq, 4.4 ꢀmol, 3.0 mg),
2
νmax/cm : 3306 (O-H), 2840 (=C-H ), 1692 (C=O), 1593
Ar
Xantphos (0.1 eq, 4.4 ꢀmol, 3.0 mg) and DABCO (2 eq, 88
mol, 10 mg). The chamber 2 was sealed with a screwcap fitted
(
C=C ), 1190 (C-O).
Ar
ꢀ
with a silicone/PTFE seal. The atmosphere of the two-chamber
system was purged three times with nitrogen. Then, 1 mL of
anhydrous THF was added by syringe in each chamber through
the silicone/PTFE seal. The loaded two-chamber system was
stirred at 70 °C, then 11 µl of a solution of TBAF (1M in THF,
25 mol%, 11 µmol) were added through a silicone/PTFE seal in
the chamber 1. The system was stirred at 70°C for 1 hour. After a
careful opening, the crude reaction mixture from chamber 2 was
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (petroleum ether/ethyl acetate :
4
.13. 4-(Hydroxymethyl)benzaldehyde (19)
Under nitrogen atmosphere, suspension of 1,4-
a
benzenedimethanol (1 eq, 1.00 mmol, 138 mg) and MnO (1.5
2
eq, 1.50 mmol, 130 mg) in 17 mL of anhydrous dichloromethane
was stirred at reflux for two days. The resulting mixture was
filtrated under vacuum, the solid was washed with
dichloromethane and ethyl acetate and the filtrate was
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (petroleum ether/ethyl acetate :
13
8
0/20 to 70/30) to give 4-(hydroxymethyl)benzaldehyde 19 (63
80/20 to 70/30) to give the BODIPY [ C]24 (12 mg, 80%) as an
mg, 46%) as a colorless solid; Rf (ethyl acetate/petroleum ether :
orange solid; mp : 268 °C; R (ethyl acetate /petroleum ether :
f

9
1
4
7
1
0/60) 0.35; H NMR (300 MHz, CDCl ) δ (ppm): 7.90 (m, 1H),
thiosulfate (0.1M). The aqueous layer was extracted three times
3
.65 (m, 2H), 6.00 (s, 2H), 5.44 (d, J = 2.0 Hz, 2H), 2.57 (s, 6H),
.32 (s, 6H); C NMR (75.3 MHz, CDCl ) δ (ppm): 170.2 ( C-
with ethyl acetate. The combined organic layers were washed
with brine, dried over anhydrous Na SO and concentrated under
13
13
3
2
4
enriched), 156.6, 147.2, 142.7, 139.1, 136.6, 134.3, 131.4, 127.4,
26.5, 125.9, 123.3, 121.9, 69.8, 29.8, 15.0, 14.8; HRMS (ESI):
reduced pressure to give methyl 4-(hydroxymethyl)-3-
1
iodobenzoate 27 (1.02 g, 87%) as a brown solid; R (ethyl
f
13
11
+
1
C20 CH O N BF [M+Na] , calculated 404.1433, found
acetate/petroleum ether : 20/80) 0.28; H NMR (300 MHz,
19
2
2
2
-
1
4
1
04.1432; νmax/cm : 2924 (=C-H ), 1722 (C=O), 1547 (C=C ),
193 (C-O), 1157 (C-N).
CDCl ) δ (ppm): 8.47 (d, J = 1.7 Hz, 1H), 8.04 (dd, J = 8.0, J =
Ar
Ar
3
1.7 Hz, 1H), 7.57 (d, J = 8.0 Hz, 1H), 4.71 (d, J = 5.7 Hz, 2H),
3
.92 (s, 3H). The spectral data was in accordance with the
29
literature.
4
.17. 2-Amino-4-(methoxycarbonyl)benzoic acid (25)
Under nitrogen atmosphere, to suspension of 2-
a
4
.20. Methyl 3-amino-4-(hydroxymethyl)benzoate (28)
Under a nitrogen atmosphere, to a solution of 2-amino-4-
aminoterephthalic acid 18 (1 eq, 10 mmol, 1.81 g) in 40 mL of
methanol was added TMSCl (1.5 eq, 15 mmol, 1.9 mL). The
resulting mixture was stirred at reflux overnight and concentrated
under reduced pressure. The residue was dissolved in a saturated
aqueous solution of sodium bicarbonate and the aqueous layer
was extracted three times with ethyl acetate, and the combined
organic layers were washed with a saturated aqueous solution of
sodium bicarbonate. The combined aqueous layers were acidified
with acetic acid until neutral pH, and extracted three times with
ethyl acetate, the combined organic layers were washed with
(methoxycarbonyl)benzoic acid 25 (1 eq, 5.00 mmol, 976 mg)
and I (1 eq, 5.00 mmol, 1.27 g) in 30 mL of anhydrous THF was
added NaBH (2.5 eq, 12.5 mmol, 473 mg) at 0 °C. The resulting
mixture was stirred at reflux overnight. After returning to room
temperature, the reaction mixture was diluted with 30 mL of
ethyl acetate and quenched with 30 mL of a saturated aqueous
solution of ammonium chloride at 0 °C. The layers were
separated and the organic layer was washed with distilled water.
The combined aqueous layers were extracted twice with ethyl
acetate, dried over anhydrous Na SO and concentrated under
2
4
brine, dried over anhydrous Na SO4 and concentrated under
2
reduced pressure to give 2-amino-4-(methoxycarbonyl)benzoic
2
4
acid 25 (1.7 g, 87%) as
acetate/petroleum ether/acetic acid : 40/60/1) 0.55; H NMR (300
a
yellow solid; Rf (ethyl
reduced pressure. The residue was purified by silica gel column
chromatography (petroleum ether/ethyl acetate : 60/40 to 50/50)
to give methyl 3-amino-4-(hydroxymethyl)benzoate 28 (730 mg,
1
MHz, DMSO-d ) δ (ppm) : 7.78 (d, J = 8.3 Hz, 1H), 7.40 (d, J =
6
1
.6 Hz, 1H), 7.02 (dd, J = 8.3, J = 1.6 Hz, 1H), 3.83 (s, 3H). The
81%) as a yellow solid; mp : 103 °C; R (ethyl acetate/petroleum
f
28
1
spectral data was in accordance with the literature.
ether : 60/40) 0.34; H NMR (300 MHz, CDCl ) δ (ppm): 7.39
3
13
(m, 2H), 7.14 (d, J = 8.0 Hz, 1H), 4.72 (s, 2H), 3.89 (s, 3H);
C
4
.18. 2-Iodo-4-(methoxycarbonyl)benzoic acid (26)
NMR (75.3 MHz, CDCl ) δ (ppm): 167.3, 146.1, 130.9, 129.4,
3
+
1
29.0, 119.4, 116.9, 64.0, 52.2; HRMS (ESI): C H O N [M+H] ,
9 11 3
-1
To a suspension of 2-amino-4-(methoxycarbonyl)benzoic acid
5 (1 eq, 0.50 mmol, 98 mg) in 3 mL of distilled water was
calculated 182.0812, found 182.0812; νmax/cm : 3355 (N-H),
211 (O-H), 2948 (=C-H ), 1707 (C=O), 1440 (N-H), 1301 (C-
2
3
added p-TsOH.H O (3 eq, 1.50 mmol, 286 mg). The resulting
mixture was stirred at room temperature for 5 min and NaNO2
Ar
2
N), 1248 (C-O).
(
2.5 eq, 1.3 mmol, 87 mg) was added at 0 °C. The reaction
Acknowledgments
mixture was stirred at room temperature for 10 min and KI (2.5
eq, 1.30 mmol, 208 mg) was added. The resulting dark brown
solution was stirred at room temperature overnight and was
quenched with 7 mL of an aqueous solution of sodium thiosulfate
This study was supported by the “Ministère de
l’Enseignement et de la Recherche” (PhD grants for T. Ch. and
T. Co.), by a public grant from the French Agence Nationale de
la Recherche referenced ANR-15-CE18-0015-01 (SuCarB, PhD
grant for A.T.) and realized within the context of the Investments
for the Future Program (referenced ANR-10-LABX-57 and
named TRAIL). NMR and mass analyses were performed at the
CESAMO (ISM UMR 5255).
(
0.1M). The aqueous layer was extracted with ethyl acetate,
slightly acidified with an aqueous solution of hydrochloric acid
1M) to pH 4-5, and once again extracted three times with ethyl
(
acetate, the combined organic layers were dried over anhydrous
Na SO and concentrated under reduced pressure to give the 2-
2
4
iodo-4-(methoxycarbonyl)benzoic acid 26 (107 mg, 70%) as a
brown solid; mp : 141 °C; R (ethyl acetate/petroleum ether/acetic
References and notes
f
1
acid : 40/60/1) 0.24; H NMR (300 MHz, CDCl ) δ (ppm): 8.69
3
(
8
1
d, J = 1.5 Hz, 1H), 8.08 (dd, J = 8.2, J =1.5 Hz, 1H), 8.02 (d, J =
1. (a) Hood, L.; Heath, J. R.; Phelps, M. E.; Lin, B. Science 2004,
13
3
06, 640-643; (b) Sanabria Bohorquez, S. M.; van Bruggen, N. ;
.2 Hz, 1H), 3.96 (s, 3H); C NMR (75.3 MHz, CDCl ) δ (ppm):
3
Marik, J. In Medicinal Chemistry Approaches to Personalized
Medicine; Lackey, K.; Roth, B.; Eds.; Wiley‐VCH Verlag GmbH
& Co. KGaA, 2014, pp. 289-342; (c) Collins, F. S.; Varmus, H.;
N. Engl. J. Med. 2015, 372, 793-795.
70.0, 164.9, 142.8, 137.3, 134.4, 131.7, 129.1, 94.2, 52.9;
1
27
-
HRMS (ESI): C H O I [M-H] , calculated 304.9316, found
3
9
7
4
-
1
04.9308; νmax/cm : 3047 (=C-H ), 2543 (O-H), 1722
Ar
(
C=Oester), 1538 (C=C ), 1699 (C=Oacide), 1287 (C-O).
2. (a) PET Chemistry, The Driving Force in Molecular Imaging;
Schubiger, P. A.; Lehmann, L.; Friebe, M.; Eds; Springer-Verlag,
Berlin Heidelberg, 2007; (b) Ametamey, S. M.; Honer, M.;
Schubiger, P. A. Chem. Rev. 2008, 108, 1501-1516; (c) Li, Z.;
Conti, P. S. Adv. Drug Deliv. Rev. 2010, 62, 1031-1051.
3. (a) Licha, K.; Olbrich, C. Adv. Drug Deliv. Rev., 2005, 57, 1087-
Ar
4
.19. Methyl 4-(hydroxymethyl)-3-iodobenzoate (27)
To suspension of methyl
a
3-amino-4-
(hydroxymethyl)benzoate 28 (1 eq, 4.00 mmol, 730 mg) in 50
1
108; (b) Ntziachristos, V.; Ripoll, J.; Wang, L. V.; Weissleder, R.
mL of distilled water was added p-TsOH.H O (3 eq, 12.0 mmol,
2
for 5 min and NaNO (2.5 eq, 10.0 mmol, 690 mg) was added at
0
min and KI (2.5 eq, 10.0 mmol, 1.66 g) was added. The resulting
dark brown solution was stirred at room temperature overnight
and was quenched with 50 mL of an aqueous solution of sodium
2
Nat. Biotechnol. 2005, 23, 313-320; (c) Luker, G. D.; Luker, K. E.
J. Nucl. Med. 2008, 49, 1-4.
.28 g). The resulting mixture was stirred at room temperature
2
4. For selected reviews on the design of fluorescent probes, see: (a)
Kobayashi, H.; Ogawa, M.; Alford, R.; Choyke, P. L.; Urano, Y.
Chem. Rev. 2010, 110, 2620-2640; (b) Lavis, L. D. Biochemistry
°C. The reaction mixture was stirred at room temperature for 10
2
017, 56, 5165-5170.

10
Tetrahedron
5
6
.
.
(a) Nagaya, T.; Nakamura, Y. A.; Choyke, P. L.; Kobayashi, H.
Front. Oncol. 2017, 7, 314; (b) Low, P. S.; Singhal, S.;
J. Org. Biomol. Chem. 2015, 13, 9528-9550; (f) Sing, M. S.;
Chowdhury, S.; Koley, S. Tetrahedron 2016, 72, 5257-5283.
16. del Río, M.; Lobo, F.; Lopez, J. C.; Oliden, A.; Banuelos, J.;
Lopez-Arbeloa, I; Garcia-Moreno, I.; Gomez, A. M. J. Org.
Chem. 2017, 82, 1240-1247.
Srinivasarao, M. Curr. Opin. Chem. Biol. 2018, 45, 64-72.
For selected recent examples, see: (a) Pandey, S. K.; Gryshuk, A.
L.; Sajjad, M.; Zheng, X.; Chen, Y.; Abouzeid, M. M.; Morgan, J.;
Charamisinau, I.; Nabi, H. A.; Oseroff, A.; Pandey, E. K. J. Med.
Chem. 2005, 48, 6286-6295 (b) Sampath, L.; Kwon, S.; Ke, S.;
Wang, W.; Schiff, R.; Mawad, M. E.; Sevick-Muraca, E. M. J.
Nucl. Med. 2007, 48, 1501-1510; (c) Liu, Z.; Radtke, M. A.;
Wong, M. Q.; Lin, K.-S.; Yapp, D. T.; Perrin, D. M. Bioconjugate
Chem. 2014, 25, 1951-1962; (d) Rodriguez, E. A.; Wang, Y.;
Crisp, J. L.; Vera, D. R.; Tsien, R. Y.; Ting, R. Bioconjugate
Chem. 2016, 27, 1390-1399; (e) Sun, Y.; Zeng, X.; Xiao, Y.; Liu,
C.; Zhu, H.; Zhou, H.; Chen, Z.; Xu, F.; Wang, J.; Zhu, M.; Wu,
J.; Tian, M. Zhang, H.;Deng, Z.; Cheng, Z.; Hong, X. Chem. Sci.,
17. (a) Hermange, P.; Lindhardt, A. T.; Taaning, R. H.; Bjerglung, K.;
Lupp, D.; Skrydstrup, T. J. Am. Chem. Soc. 2011, 133, 6061-6071;
(b) Friis, S. D.; Taaning, R. H.; Lindhardt, A. T.; Skrydstrup, T. J.
Am. Chem. Soc. 2011, 133, 18114-18117; (c) Friis, S. D.;
Lindhardt, A. T.; Skrydstrup, T. Acc. Chem. Res. 2016 49, 594-
605.
11
18. [ C]6 could be isolated in 71% radiochemical yield from
substrate 5 after oxidative addition with stoichiometric amounts of
3 4
Pd(PPh ) and ligand exchange with polystyrene-supported
triphenylphosphine. See reference 12c for details.
19. (a) Cai, R.; Lu, M.; Aguilera, E. Y.; Xi, Y.; Akhmedov, N. G.;
Petersen, J. L.; Chen, H.; Shi, X. Angew. Chem. Int. Ed. 2015, 54,
8772-8776; (b) Cornilleau, T.; Hermange, P.; Fouquet, E. Chem.
Commun. 2016, 52, 10040-10043; (c) Gauchot, V.; Lee, A.-L.
Chem. Commun. 2016, 52, 10163-10166; (d) Witzel, S.; Xie, J.;
Rudolph, M.; Hashmi, A. S. K. Adv. Synth. Catal. 2017, 359,
1522-1528; (e) Sauer, C.; Liu, Y.; De Nisi, A.; Protti, S.; Fagnoni,
M.; Bandini, M. ChemCatChem 2017, 9, 4456-4459; (f) Tabey,
A.; Berlande, M.; Hermange, P.; Fouquet, E. Chem. Commun.
2018, 54, 12867-12870.
20. (a) Prokopcová, H.; Kappe, C. O. Angew. Chem. Int. Ed. 2009, 48,
2276-2286; (b) Roacho, R. I.; Metta‐Magana, A. J.; Pena‐Cabrera,
E.; Pannell, K. H. J. Phys. Org. Chem. 2013, 26, 345-351 (c)
Cheng, H.-G.; Chen, H.; Liu, Y.; Zhou, Q. Asian J. Org. Chem.
2018, 7, 490-508.
21. (a) Peña-Cabrera, E.; Aguilar-Aguilar, A.; Gonzalez-Dominguez,
M.; Lager, E.;. Zamudio-Vazquez, R; Godoy-Vargas, J.;
Villanueva-Garcia, F. Org. Lett. 2007, 9, 3985-3988; (b) Han, J.
Y.; Gonzalez, O.; Aguilar-Aguilar, A.; Peña-Cabrera, E.; Burgess,
K. Org. Biomol. Chem. 2009, 7, 34-36; (c) Betancourt-Mendiola,
L.; Valois-Escamilla, I.; Arbeloa, T.; Bañuelos, J.; López Arbeloa,
I.; Flores-Rizo, J. O.; Hu, R.; Lager, E.; Gómez-Durán, C. F. A.;
Belmonte-Vázquez, J. L.; Martínez-González, M. R.; Arroyo, I. J.;
Osorio-Martínez, C. A.; Alvarado-Martínez, E.; Urías-Benavides,
A.; Gutiérrez-Ramos, B. D.; Tang, B. Z.; Peña-Cabrera, E. J. Org.
Chem. 2015, 80, 5771-5782.
2
018, 9, 2092-2097.
7
8
.
.
For selected reviews on BODIPY, see: (a) Loudet, A.; Burgess, K.
Chem. Rev. 2007, 107, 4891-4932; (b) Kowada, T.; Maeda, H.;
Kikuchi, K. Chem. Soc. Rev. 2015, 44, 4953; (c) Boens, N.;
Verbelen, B.; Dehaen, W. Eur. J. Org. Chem. 2015, 6577-6595.
For examples, see: (a) Li, Z.; Lin, T.-P.; Liu, S.; Huang, C.-W.;
Hudnall, T. W.; Gabbaï, F. P.; Conti, P. S. Chem. Commun. 2011,
4
7, 9324-9326; (b) Hendricks, J. A.; Keliher, E. J.; Wan, D.;
Hilderbrand, S. A.; Weissleder, R.; Mazitschek, R. Angew. Chem.
Int. Ed. 2012, 51, 4603-4606; (c) Liu, S.; Lin, T.-P.; Leamer, L.;
Shan, H.; Li, Z.; Gabbai, F. P.; Conti, P. S. Theranostics 2013, 3,
1
81-189; (d) Brizet, B.; Goncalves, V.; Bernhard, C.; Harvey, P.
D.; Denat, F.; Goze, C. Chem. Eur. J. 2014, 20, 12933-12944. (e)
Chansaenpak, K.; Wang, H.; Wang, M.; Giglio, B.; Ma, X.; Yuan,
H.; Hu, S.; Wu, Z. Li, Z. Chem. Eur. J. 2016, 22, 12122-12129.
(a) Lhenry, D.; Larrouy, M.; Bernhard, C.; Goncalves, V.; Raguin,
O.; Provent, P.; Moreau, M.; Collin, B.; Oudot, A.; Vrigneaud,
M.; Brunotte, F.; Goze, C.; Denat, F. Chem. Eur. J. 2015, 21,
9
.
1
3091-13099; (b) Maindron, N.; Ipuy, M.; Bernhard, C.; Lhenry,
D.; Moreau, M.; Carme, S.; Oudot, A.; Collin, B.; Vrigneaud, J.-
M.; Provent, P.; Brunotte, F.; Denat, F.; Goze, C. Chem. Eur. J.
2
016, 22, 12670-12674; (c) Bertrand, B.; Passador, K.; Goze, C.;
Denat, F.; Bodio, E.; Salmain, M. Coord. Chem. Rev. 2018, 358,
08-124.
1
1
1
1
1
0. For reviews on [ C]CO carbonylations see: (a) Kealy, S.; Gee, A.;
Miller, P. W. J. Labelled Compd. Radiopharm. 2014, 57, 195-201;
(b) Rahman, O. J. Labelled Compd. Radiopharm. 2015, 58, 86-98;
22. Erb, W.; Hellal, A.; Albini, M.; Rouden, J.; Blanchet, J. Chem.
Eur. J. 2014, 25, 6608-6612.
23. Goud, T. V.; Tutar, A.; Biellmann, J.-F. Tetrahedron 2006, 62,
5084-5091.
24. Stanetty, P.; Rodler, I.; Krumpak, B. J. Prakt. Chem.-Chem. Ztg.
1993, 335, 17-22.
25. Stavber, S.; Jereb, M.; Zupan, M. Synthesis 2008, 10, 1487-1513.
26. Kraszkiewicz, L.; Sosnowski, M.; Skulski, L. Synthesis 2006, 7,
1195-1199.
(c) Rostein, B. H.; Liang, S. H.; Placzek, M. S.; Hooker, J. M.;
Gee, A. D.; Dollé, F.; Wilson, A. A.; Vasdev, N. Chem. Soc. Rev.
016, 45, 4708-4726; (d) Nielsen, D. U.; Neumann, K. T.;
2
Skrydstrup, T. Chimia 2018, 72, 606-609.
1. For selected examples of palladium-catalyzed intramolecular
1
1
alkoxycarbonylation with [ C]CO, see: (a) Kihlberg, T.;
Lidström, P.; Långström, B. J. Labelled Compd. Radiopharm.
1
997 40, 781-782; (b) Hostetler, E. D.; Burns, H. D. Nucl. Med.
Biol. 2002, 29, 845-848; (c) Audrain, H.; Martarello, L.; Gee, A.;
Bender, D. Chem Commun. 2004, 7, 558-559; (d) Dahl, K. ;
Schou, M.; Amini, N.; Halldin, C. Eur. J. Org. Chem. 2013, 1228-
27. Ueno, T.; Urano, Y.; Kojima, H.; Nagano, T. J. Am. Chem. Soc.
2006, 128, 10640-10641.
28. Ursuegui, S.; Yougnia, R.; Moutin, S.; Burr, A.; Fossey, C.;
Cailly, T.; Laayoun, A.; Laurent, A.: Fabis, F., Org. Biomol.
Chem. 2015, 13, 3625-3632.
29. Konishi, H.; Tanaka, H.; Manabe, K. Org. Lett.2017, 19,1578-
1581.
30. Jeon A. R., Kim M. E., Park J. K., Shin W. K., An D. K.
Tetrahedron 2014, 70, 4420-4424.
1
231.
1
1
2. (a) Cornilleau, T.; Audrain, H.; Guillemet, A.; Hermange, P.;
Fouquet, E. Org. Lett. 2015, 17, 354-357; (b) Cornilleau, T.;
Simonsen, M.; Vang, M.; Taib-Maamar, N.; Dessolin, J.; Audrain,
H.; Hermange, P.; Fouquet, E. Bioconjugate Chem. 2017, 28,
2
887-2894; (c) Tabey, A.; Audrain, H.; Fouquet, E.; Hermange, P.
Chem Commun. 2019, 55, 7587-7590.
31. Kawabata E., Kikuchi K., Urano Y., Kojima H., Odani A., Nagano
T., J. Am. Chem. Soc., 2005, 127, 818-819
32. Kommreddy, A.; Bowsher, M. S.; Gunna, M. R.; Botha, K.;
Vinod, T. K. Tetrahedron Lett. 2008, 49, 4378-4382
33. Schweez, C.; Shushkov, P.; Grimme, S.; Höger, S. Angew. Chem.
Int. Ed. 2016, 55, 3328-3333
3. (a) Courtis, A. M.; Santos, S. A.; Guan, Y.; Hendricks, J. A.;
Ghosh, B.; Szantai-Kis, D. M.; Reis, S. A.; Shah, J. V.;
Mazitschek, R. Bioconjugate Chem. 2014, 25, 1043-1051; (b)
Meimetis, L. G.; Boros, E.; Carlson, J. C.; Ran, C.; Caravan, P.;
Weissleder, R. Bioconjugate Chem. 2015, 27, 257-263.
4. Cormier, M.; Fouquet; E, Hermange, P. Org. Chem. Front. 2019,
1
1
6
, 1114-1117.
Supplementary Material
5. (a) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B.
Angew. Chem. Int. Ed. 2002, 41, 2596-2599; (b) Tornøe, C. W.;
Christensen, C.; Meldal, M. J. Org. Chem. 2002, 67, 3057-3064;
For selected reviews, see: (c) Meldal, M.; Tornøe, C. W. Chem.
Rev. 2008, 108, 2952-3015; (d) Hein., J. E.; Fokin, W. Chem. Soc.
Rev. 2010, 39, 1302-1315; (e) Haldon, E.; Nicasio, M. C; Pérez, P.
Spectra of absorbance / emission, and determination of the
13
13
13
1
13
quantum yields for [ C]6, [ C]14 and [ C]24. H and C NMR
spectra of new compounds.

-
Syntheses of o-iodobenzyl alcohols‒BODIPY structures as potential precursors for
11
multimodal imaging tags (fluorescence / C-labeling).
“Coupling” and “BODIPY formation” strategies explored
Most promising structure obtained in five steps from commercially available starting
materials.
-
-

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: