Functionalized BF2 chelated azadipyrromethene dyes

Article abstract of DOI:10.1016/j.tet.2008.01.117

Fluorescent molecules that emit in the near infrared are potentially useful as probes for biotechnology. A relatively under-explored design for probes of this type are the aza-BODIPY dyes; this study was performed to enhance our understanding of these materials and ways in which they may be used in dye cassette systems. Thus, the aza-BODIPY dyes 1a-g were prepared. An advanced intermediate toward an eighth compound in the series, 6h, was made but it could not be complexed with boron effectively to give 1h. Spectroscopic properties of these compounds were recorded, and correlations between substituent effects, UV absorbance, fluorescence emissions, and quantum yields were made. Compound 1a was coupled with a fluorescein-alkyne derivative to give the energy transfer cassettes 2 and 3. Both these compounds gave poor energy transfer and the possible reasons for this were discussed.

Full text of DOI:10.1016/j.tet.2008.01.117

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 3642e3654
www.elsevier.com/locate/tet
Functionalized BF2 chelated azadipyrromethene dyes
*
Aurore Loudet, Rakeshwar Bandichhor, Liangxing Wu, Kevin Burgess
Department of Chemistry, Texas A & M University, PO Box 30012, College Station, TX 77841-3012, United States
Received 27 November 2007; received in revised form 29 January 2008; accepted 30 January 2008
Available online 3 February 2008
Abstract
Fluorescent molecules that emit in the near infrared are potentially useful as probes for biotechnology. A relatively under-explored design for
probes of this type are the aza-BODIPY dyes; this study was performed to enhance our understanding of these materials and ways in which they
may be used in dye cassette systems. Thus, the aza-BODIPY dyes 1aeg were prepared. An advanced intermediate toward an eighth compound
in the series, 6h, was made but it could not be complexed with boron effectively to give 1h. Spectroscopic properties of these compounds were
recorded, and correlations between substituent effects, UV absorbance, fluorescence emissions, and quantum yields were made. Compound 1a
was coupled with a fluoresceinealkyne derivative to give the energy transfer cassettes 2 and 3. Both these compounds gave poor energy transfer
and the possible reasons for this were discussed.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Fluorescent compounds; Biochemical markers; Heterocyclic compounds
1. Introduction
however, has limitations. For instance, amine groups make
the probes sensitive to quenching via electron transfer to the
excited state, and the fluorescence becomes pH sensitive.
There is a subset of BODIPY dyes that are related to the par-
ent systems by N-for-C substitution at the C8-position. These are
commonly called ‘aza-BODIPY’dyes, and almost all the known
compounds have 3,3,5,5-aryl substituents, of which the tetra-
phenyl system B is the most widely studied. The parent hetero-
cyclewithout a boron atom has been known since 1943,12e15 but
it was not until 1994 that a B-derivativewas mentioned in the lit-
erature and its remarkable fluorescent properties were noted.16
Specifically, the tetraphenyl compound B was shown to emit
at 695 nm (in 1,2-Me2C6H4, F¼0.77), i.e., a marked red-shift
relative to other BODIPY dyes.
There is considerable interest in preparing new fluorescent
dyes that emit toward the near-IR region.1e4 Labeled-biomol-
ecules are more easily observed in vivo, for instance, when the
probes used emit in this region.5 Unfortunately, there are
a very limited number of organic molecules that emit in this
range and could be adapted to form probes for biomolecules.
Probably, the most widely used are the cyanine dyes,6e10
and few other choices are commercially available.
BODIPY (difluoroboradiaza-s-indacene) dyes A are highly
fluorescent, stable, and insensitive to the solvents’ polarity and
pH. BODIPYs are unusual in that they are relatively non-polar
and are electronically neutral. They have found widespread
applications as laser dyes, sensors, and molecular probes
that emit in the region around 520e600 nm.11
Ar1
Ar1
N
Ph
5
Ph
5
8
N
N
N
Modifications to the BODIPY core can lead to dyes that
emit above 600 nm. Such modifications include appending
strong electron-donating groups, rigidifying substituents
around the core, and extending the conjugation of the system.
The strategy of attaching electron-donating substituents,
B
N
N
N
N
F2
3
3
Ph
B
B
F2
F2
Ph
B
C
A
BODIPY skeleton
aza-BODIPY
ortho-xylene ; Φ 0.77
λmax abs 653 nm
"constrained"
aza-BODIPY
λmax emis 690 - 815 nm
* Corresponding author.
E-mail address: burgess@tamu.edu (K. Burgess).
λmax emis 695 nm
0040-4020/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.01.117

A. Loudet et al. / Tetrahedron 64 (2008) 3642e3654
3643
Ph
5
Ph
MeO
OMe
Ar
5
Ar
5
N
5
N
B
N
N
N
N
3
3
3
3
B
700 nm
F2
N
O O
N
N
B
Me2N
NMe2
F2
D
E
"cyclized" aza-BODIPY
MeC6H5; Φ 0.35 - 0.51
λmax emis 746 - 776 nm
pH sensitive probe
CHCl3; no Φ reported
λmax emis 823 nm
488 nm
488 nm
+K-O
CHCl3 + TFA
λmax emis 753 nm (E-H+)
λmax emis 668 nm (E-2H+)
CO2-K+
CO2-K+
O
O
O
To date, there have been only two deliberate attempts to
further extend the emission of aza-BODIPY dyes into the
near-IR region. First, Carreira and Zhao used extended hetero-
cycles to prepare constrained systems such as C; this gave
molecules that emitted up to 815 nm with enhanced quantum
yields.17,18 Second, work from our laboratory was focused on
using ortho-oxygens on the 3,3-aryl substituents to constrain
them giving systems D; this approach also shifts the fluores-
cence emissions to the red and increased the quantum yields.19
Finally, when designing pH sensitive probes, O’Shea found
that when 4-N,N-dimethylaminobenzene substituents were
created at the 3,3-aza-BODIPY sites in molecule E, then an
emission at 823 nm was observed under conditions where
the amine groups were not protonated.20 This was reported
while the work described in this paper was in progress. Com-
pound E has limited value as a potential core-structure for
biomolecular probes unless protonated, in which case the
red-shift is not observed. Nevertheless, that observation sup-
ported the hypothesis we were exploring, i.e., strongly elec-
tron-withdrawing or electron-donating aryl substituents could
significantly shift the emissions of aza-BODIPY dyes. A sec-
ond goal of this study was to prepare aza-BODIPY systems
with halide substituents that could be substituted with ‘donor’
fragments that absorb considerably shorter UV radiation. In
the event, both these goals were realized, and the data are
reported here. Specifically, a series of aza-BODIPY dyes
1aeg, having a range of different substituted-aryl groups were
prepared. One of these potential ‘acceptor’ molecules, com-
pound 1a was elaborated into the donoreacceptor cassette21e23
systems 2 and 3. Important spectral parameters for all these
dyes are reported here.
+K-O
O
2
O
O
HO2C
CO2H
handle to attach
to biomolecules
700 nm
N
N
N
B
F2
488 nm
488 nm
CO2H
CO2H
O
HO
O
O
O
HO
3
2. Results and discussion
2.1. Synthesis of aza-BODIPYS 1aeg
Synthesis of dyes 1 began with diaryl a,b-unsaturated
ketones 4 (chalcones; readily prepared by an aldol/dehydration
reaction of the corresponding benzaldehyde and acetophenone
derivatives). O’Shea’s modification24 of an older Rogers’ pro-
cedure was then used.12 Thus, Michael addition of the anion
from nitromethane to the chalcones 4 gave the 1,3-diaryl-4-ni-
trobutan-1-ones 5 in essentially quantitative yields after aque-
ous work-up; these were then used without further purification.
Condensation with ammonium acetate in refluxing butanol
gave the azadipyrromethenes 6 via a cascade of events (in
situ formation of the pyrrole and corresponding nitroso-
pyrrole, and subsequent condensation of those two entities).
Finally, complexation of the azadipyrromethenes with boron
trifluoride gave the aza-BODIPYs 1 in excellent yields.
Using the procedure outlined in Scheme 1, dipyrromethene
intermediate 6h was only obtained in low yield (8%, crude)
R1
R1
cpd
R1
R2
R3
OMe
Br
H
I
H
H
a
b
c
OMe
H
N
OMe
OMe
OMe
OMe
OMe
H
N
N
R3
Br
I
Br
Br
Br
H
H
OMe
NMe2
I
R3
d
e
f
B
F2
R2
g
R2
ha
1
a
compound 1h could not be obtained. Compound 6h could however be obtained.

3644
A. Loudet et al. / Tetrahedron 64 (2008) 3642e3654
Br
I
R1
R2
O
H
O
HO
CN
acetone
KOH
+
+
R3
10% Na2CO3, reflux
12 h
EtOH:H2O
reflux, 12h
O
O
R3
R1
R2
4a- h 70 - 80 %
Br
Br
I
NH2OH•HCl, MeOH, 100 °C, 3 d
R1
R2
CN
O
MeNO2, KOH
EtOH, reflux, 12 h
NH4OAc
BuOH, reflux, 24 h
7
40 %
O
R3
O2N
Br
Br
Br
5a - h ca. 100 %
BF3•OEt2
EtiPr2N
R1
R1
R1
R1
N
N
NH
N
N
N
CH2Cl2
25 °C, 24 h
B
F2
· HCl
BF3•OEt2
EtiPr2N
N
NH
N
N
N
N
CH2Cl2
25 °C, 24 h
R3
R3
R3
R3
B
I
I
I
I
F2
6h•HCl 32 %
1h
R2
R2
R2
R2
I
6a - h ca. 50 %
1a - g ca. 98 %
Br
Scheme 1. Syntheses of aza-BODIPY 1aeg.
N
Br
and in an impure form, so other conditions were developed
(Scheme 2). Variations of solvent (butanol, pentanol, hexanol,
neat), ammonia source (HCONH2 instead of NH4OAc), and
heating conditions (conventional heating or microwave radia-
tion) to make the reaction viable were unsuccessful. However,
6h$HCl was obtained from the g-ketonitrile 7 (made from the
corresponding chalcone and acetone cyanohydrin) via conden-
sation with hydroxylamine hydrochloride in methanol; this is
one of the procedures developed by Rogers in 1944.13,25 Sur-
prisingly, complexation of 6h with boron trifluoride etherate
did not give the desired product, but instead led to a compound
with two BF2 units (19F); the structure of this adduct was ten-
tatively assigned as 8. Presumably steric and/or electronic
interactions within 6h prevented formation of the desired aza-
BODIPY 1h, an observation supported by the fact that when
the iodo groups were substituted (via Sonogashira, for example)
prior to complexation, formation of the aza-BODIPY proceeds
easily and in good to excellent yield (data not shown).
B
F2
N
N
BF2
I
8
Scheme 2. Modified route for the preparation of aza-BODIPY 1h.
2 and 3, vide infra), consequently most of them contain halo-
gen atoms. However, this series of compounds does provide
some non-systematic basis for comparing absorption and fluo-
rescence properties.
Absorption spectra of compounds 1 show strong S0/S1
transitions with absorbance maxima between 650 and
798 nm (Table 1 and Fig. 2a). Entries 1 and 2 in Table 1 are
literature data24 for the tetra-aryl substituted aza-BODIPYs
B and F.
Compounds 1aeg have good solubilities in most organic
solvents (e.g., chloroform, toluene, tetrahydrofuran). An X-ray
structure of compound 1a is shown in Figure 1. Compound
1a crystallized in the triclinic space group P-1 with two mol-
ecules in the asymmetric unit. The overall conjugated nature
of the chromophore was confirmed from the analysis of the
crystal structure with comparable bond lengths.
Using these as references, the data collected on compounds
1 indicate that introduction of electron-donating groups onto
the aryl substituents results in significant bathochromic shifts.
N
N
N
N
N
N
2.2. Spectroscopic properties of aza-BODIPY derivatives
1aeg
B
B
F2
F2
Compounds 1 were prepared mainly to facilitate the synthe-
ses of more elaborate molecules containing donor groups (e.g.,
OMe
MeO
B
F

A. Loudet et al. / Tetrahedron 64 (2008) 3642e3654
3645
Figure 1. X-ray structure of 1a. The molecule exists in two O-Me conformations in the crystal lattice.
(a) 1.2
Table 1
Key spectroscopic data for the aza-BODIPY derivatives 1aeg
1a
1b
1c
1d
1e
1f
R1
substn of H
R1
1
0.8
0.6
0.4
0.2
0
by OMe:
red shift
N
substn of H
by OMe:
N
N
1g
R3
R3
B
F2
blue shift
substn of H
by OMe:
R2
R2
large red shift
1
Entry
Dye
labs
3 (Mꢀ1 cmꢀ1
)
lemis
Fwhma
(nm)
Fb
(nm)
(nm)
400
500
600
700
Wavelength (nm)
800
900
1
2
3
4
5
6
7
8
9
a
B
655
693
680
702
640
650
653
692
798
79,000
85,000
109,000
84,120
73,850
55,000
71,600
66,200
68,610
676
717
711
731
688
694
701
738
830
d
d
47
30
47
47
35
50
30
0.34
0.36
F
1a
1b
1c
1d
1e
1f
1g
0.18ꢁ0.01
0.42ꢁ0.03
0.07ꢁ0.01
0.10ꢁ0.01
0.10ꢁ0.01
0.20ꢁ0.01
0.07ꢁ0.01
(b) 1.2
1a
1b
1c
1d
1e
1f
1
0.8
0.6
0.4
0.2
0
1g
Full width at half maximum peak height.
Measured in 1% pyridine/toluene, Zn-phthalocyanine standard (F¼0.30 in
b
the same solvent).
The largest red-shift in the series was observed for compound
1g (entry 9), which has two strongly electron-donating groups
attached to the 3-aryl substituents in ortho- and para-posi-
tions. This is consistent with the idea that the HOMO/
LUMO energy levels of the aza-BODIPY core are influenced
in such a way that fluorescence is enhanced by the electron-
rich aryl substituents. Comparison of molecules 1cee with
the rest of those in the series implies that the presence of an
ortho-methoxy group on the 3-aryl substituent correlates
with a blue-shift in the absorbance, but this may be overridden
by a strongly electron-donating group in the para-position
of the same aromatic ring. Throughout, the extinction
550
650
750
Wavelength (nm)
850
Figure 2. (a) Normalized absorption and (b) fluorescence spectra of com-
pounds 1aeg in toluene at 5 mM.
coefficients for these new dyes are high, in the range of
55,000e109,000 Mꢀ1 cmꢀ1, characteristic of aza-BODIPY
compounds.

3646
A. Loudet et al. / Tetrahedron 64 (2008) 3642e3654
Fluorescence properties of the new dyes are also shown in
2.4. Spectroscopic studies of cassette 2
Table 1, and the spectra are shown in Figure 2b. Their emis-
sion maxima range from 676 to 830 nm in toluene. Quantum
yields for compounds in this series range from 0.07 to 0.41 in
toluene. Interestingly, the fluorescence quantum yields of
the bromoaryl-substituted derivatives were not significantly
altered, while the fluorescence quantum yields of the
iodoaryl-substituted derivatives show a significant decrease.
There has been a tendency to over-generalize on the influence
of some substituents on fluorescence, and the so-called ‘heavy
atom effect’ is a prime example of this. For compounds 1,
bromine-containing aryl substituents do not reduce the quan-
tum yields to trivial values (e.g., 1b, entry 4). The only iodin-
ated analogs in the series, 1a and 1e, also have reasonable
quantum yields (0.18 and 0.10, respectively, entries 3 and
7). Most probably, the origins of the heavy atom effect are
electron donation or acceptance from excited states of the
chromophore, which often, but not always, occurs when heavy
atoms are present. For the aza-BODIPY dyes 1 the halo-sub-
stituents are isolated from the chromophore by the aryl twist.
Consequently, the main parameter influencing the fluores-
cence properties of the core is the oxidation potentials of those
aryl substituents. This more sophisticated argument, rather
than generalizations about ‘heavy atom effects’, is the one
advocated in other situations in several papers by Nagano
and co-workers.26e32
The absorption and emission spectra of cassettes 2 are sol-
vent and pH dependent, reflecting the characteristics of the
fluorescein part. This is consistent with the properties of fluo-
rescein itself.36e38 Fluorescein tends to close to its lactone
form at pH values of somewhat less than 6.5, and it is not par-
ticularly fluorescent in that state (Fig. 3). Such pH dependen-
cies are undesirable if these cassettes were to be used as
probes for imaging biomolecules.
Preliminary investigations of the spectroscopic properties
of compound 2 showed poor energy transfer from the donor
to the acceptor in a 1:1 mixture of THF/buffer pH 7.4
(Fig. 4a), i.e., weak fluorescence from the aza-BODIPY
(e.g., at 730 nm) was observed, and mostly fluorescence emis-
sion from the fluorescein was seen upon excitation of the do-
nors at 488 nm. To test if aggregation was responsible for this
poor energy transfer, a concentration study was performed. No
significant shift could be seen for both the absorption maxima
of the donor and acceptor at 502 and 702 nm, respectively
(Fig. 4b). Further, the relationship between fluorescence inten-
sity and concentration was essentially linear (Fig. 4c). How-
ever, increasing concentrations of the non-ionic detergent
Triton X-100 had significant effect on the system. The absorp-
tion peak of the fluorescein diminished with increased concen-
tration of Triton X-100 (Fig. 4d), and ultimately no peak was
observed. The fluorescence emission of the donor showed the
same tendency; and no emission was observed at high concen-
tration of Triton X-100 (Fig. 4e). On the other hand, the fluo-
rescence emission from the aza-BODIPY increased with
increasing concentration of Triton X-100 (Fig. 4f). It appears
that in the presence of the non-ionic detergent Triton X-100,
the fluorescein is converted to its non-fluorescent lactone
form. This change (from the quinoid to the lactone form)
can occur due to the presence of the polyoxyethylene group
in Triton X-100. It is well established that fluorescein dye
retains its lactone form in the presence of solvents having
oxygen groups.39,40
2.3. Synthesis of through-bond energy transfer cassettes 2
and 3
Scheme 3 shows syntheses of molecules 2 and 3 that have
donor fluorescein-derived entities attached to BODIPY cores.
These molecules were made to test their efficacy as energy
transfer cassettes. The difference between compounds 2 and
3 is only a carboxylic acid linker in the acceptor part.
Throughout, this donor fragment was derived from the ethynyl
fluorescein diacetate 9,23,33 which served as a Sonogashira34
coupling partner for the aza-BODIPY 1a or 10, respectively.
Compound 10 was obtained via a one-pot, two-step procedure
involving deprotection and alkylation of 1a. In the synthesis of
compound 10, demethylation of the aza-BODIPY 1a gave an
intermediate with two phenolic-OH groups. This was unstable
to air, hence it was alkylated without isolation at that stage.
The final step in both syntheses was removal of the acetate
groups from the fluorescein parts (potassium carbonate or
TMSOK35); in the synthesis of compound 3 this also hydro-
lyzed the methyl ester functionality. Overall, the synthesis of
cassette 2 was reasonably straightforward. However, cassette
3 was practically more difficult to prepare because of the insta-
bility of the intermediate mentioned above, and the need to
isolate the final product via RP-HPLC. We were unable to
fully and properly characterize compound 3 by NMR (1H
and 13C) in most organic solvents, including CD3CO2D and
D2O, because the compound aggregated. However, compound
12 was fully characterized. Synthesis of compound 3 was sup-
ported by mass spectrometry analysis and UV-fluorescence
properties.
3. Conclusions
These studies show that the fluorescence emissions ob-
served from aza-BODIPY dyes can be manipulated by altering
the electronic substituents on the aryl substituents. Red-shifts
in the fluorescence tend to correspond to strongly electron-do-
nating para-groups, at least for the 3-aryl substituent. A series
of seven functionalized aza-BODIPY dyes were prepared. Of
these, compound 1a proved to be a useful starting material
for attachment of alkyne-based energy transfer donor entities.
In this study, the donor was a fluorescein-derived alkyne. Cas-
settes 2 and 3 were prepared from this coupling procedure that
exhibited absorption and fluorescence characteristics that were
highly dependent on the pH and solvent media. These observa-
tions correlate with equilibria at the fluorescein part corre-
sponding to lactone formation, and to solvent polarity effects
that are influenced by the addition of the non-ionic detergent
Triton X-100. Overall, we conclude that aza-BODIPY dyes

A. Loudet et al. / Tetrahedron 64 (2008) 3642e3654
3647
(a)
(b)
MeO
OMe
MeO
OMe
HO
OH
10 eq. BBr3
PdCl2(PPh3)2
N
N
N
dry CH2Cl2
CuI
+
O
Et3N, THF
25 °C, 12 h
N
N
25 °C, 2 h
N
N
N
N
O
B
B
B
F2
F2
F2
AcO
O
OAc
I
I
I
I
I
I
1a
9
1a
unstable to air - not isolated
MeO
OMe
O
O
MeO2C
CO2Me
OMe
Br
N
O
N
10 eq. NaH, THF, 25 °C, 12 h
N
N
B
N
N
mono coupling
+
F2
B
F2
I
10 17% for 2 steps
I
O
O
O
O
AcO
OAc
25 mol% PdCl2(PPh3)2
0.5 mol% CuI
O
O
10
+
O
THF, 35 °C, 12 h
OAc
AcO
O
11 30%
OAc
O
9
AcO
MeO
OMe
O
O
MeO2C
CO2Me
N
N
N
N
B
F2
N
N
B
F2
K2CO3
11
12 eq. TMSOK
THF, 25 °C, 2 h
MeOH:THF (1:1)
25 °C, 1 h
CO2-K+
CO2-K+
O
+K-O
O
O
O
O
O
O
AcO
OAc
+K-O
O
O
O
OAc
AcO
2 quant.
12 40%
O
O
HO2C
CO2H
N
N
N
B
F2
CO2H
CO2H
OH
O
OH
O
O
O
3 95%
Scheme 3. Syntheses of (a) through-bond energy transfer system 2, and (b) system 3.

3648
A. Loudet et al. / Tetrahedron 64 (2008) 3642e3654
-
-
CO2
CO2H
CO2
CO2H
H
-O
O+
O
O
HO
O
O
HO
O
O
HO
O
dianion
pH > 9
Φ 0.93
monoanion
phenol pKa ~ 6.4
Φ 0.36
neutral
pKa < 5
Φ 0.29
cation
pKa ~ 2.1
Φ 0.9 - 1.0
O
O
HO
O
OH
lactone
Figure 3. pH dependency of fluorescein fluorescence quantum yield.
(a)
0.1
0.05
0
(b) 0.25
0.2
1400
2 uM
3 uM
4 uM
5 uM
Corrected Flu (exc 488 nm)
Corrected Flu (exc 702 nm)
UV
1200
1000
800
600
400
200
0
0.15
0.1
0.05
0
400
500
600
Wavelengths (nm)
700
800
400
500
600
Wavelengths (nm)
700
800
800
700
600
500
400
300
200
100
0
0.1
0.09
0.08
0.07
0.06
0.05
0.04
0.03
0.02
0.01
0
(c)
(d)
50 uL
fluorescence intensity (530 nm)
fluorescence intensity (730 nm)
100 uL
150 uL
250 uL
300 uL
0
1
2
Concentration (uM)
3
4
5
6
400
500
600
Wavelengths (nm)
700
800
400
350
300
250
200
150
100
50
400
350
300
250
200
150
100
50
(e)
(f)
50 uL
50 uL
100 uL
150 uL
250 uL
300 uL
100 uL
150 uL
250 uL
300 uL
0
500
0
700
600
700
Wavelengths (nm)
800
900
720
740
760
780
Wavelengths (nm)
800
820
Figure 4. Spectra of (a) UVabsorption and corrected fluorescence spectra (excitation at 488 and 702 nm) of 2 in 1:1 THF/buffer pH 7.4; (b) UVabsorption of 2 with
increasing concentration of 2 in 1:1 THF/buffer pH 7.4; (c) uncorrected fluorescence intensities (at 530 and 730 nm) versus concentration of compound 2 in 1:1
THF/buffer pH 7.4; (d) UVabsorption of compounds 2 in 1:1 THF/buffer pH 7.4 with increasing amount of Triton X-100; (e) uncorrected fluorescence intensity of
compound 2 upon excitation at 488 nm with increasing amount of Triton X-100; (f) uncorrected fluorescence intensity of compound 2 upon excitation at 702 nm
with increasing amount of Triton X-100.

A. Loudet et al. / Tetrahedron 64 (2008) 3642e3654
3649
have great potential application as biomolecular probes if they
can be modified to increase solubility in aqueous media. Fluo-
rescein is probably not a good donor for through-bond energy
transfer cassettes designed for applications around physiolog-
ical pH values, but the potential for using the aza-BODIPY
acceptor fragment in conjunction with other donor groups is
apparent.
130.7, 129.7, 124.5, 122.3, 113.8, 55.5; m/z (ESI): theoretical
mass (MþH)þ, 317.01; found, 317.02e319.02 (Br isotope).
4.1.3. 1-(2-Methoxyphenyl)-3-phenyl-2-propene-1-one (4c)
Compound 4c was prepared according to the reported pro-
cedure.44e46 The chalcone was obtained as a yellow oil (2.9 g,
60% yield). dH (500 MHz, CDCl3): 7.66e7.63 (m, 2H), 7.57e
7.59 (m, 2H), 7.47 (td, 1H, J¼7.3, 1.7 Hz), 7.42e7.38 (m,
4H), 7.04 (t, 1H, J¼7.6 Hz), 6.99 (d, 1H, J¼8.3 Hz), 3.89 (s,
3H); dC (125 MHz, CDCl3): 192.7, 157.9, 142.9, 134.9,
132.7, 130.1, 130.1, 129.0, 128.7, 128.2, 126.8, 120.5,
111.4, 55.5; m/z (HR-ESI): theoretical mass (MþH)þ,
239.1072; found, 239.1139.
4. Experimental section
4.1. General experimental procedures
All chemicals were obtained from commercial suppliers
and used without further purification. Chromatography on
silica gel was performed using a forced flow of the indicated
solvent on EM reagents silica gel 60 (230e400 mesh).
Dichloromethane was dried/degassed by passing it down an
4.1.4. 3-(4-Bromophenyl)-1-(2-methoxyphenyl)prop-2-en-1-
one (4d)
A solution of acetophenone (3.20 g, 0.027 mol) in ethanol
(27 mL) was added gradually to an aqueous solution of 10%
KOH (80 mL) at 0 ꢂC. After stirring for 30 min, 4-bromobenz-
aldehyde (5.00 g, 0.027 mol) was added to the solution and
stirred at 0 ꢂC for an additional 15 min. The reaction mixture
was then allowed to warm up to room temperature and stirred
for 12 h. The product precipitated from the reaction mixture
over the course of the reaction. It was filtered and washed
with water to afford the desired product as a white solid
(8.05 g, 94%). Both isomers (E) and (Z) were obtained. dH
(500 MHz, CDCl3): 7.64 (dd, 1H, J¼7.6, 1.9 Hz), 7.58e7.45
(m, 6H), 7.38 (d, 1H, J¼15.8 Hz), 7.05 (td, 1H, J¼7.6,
0.9 Hz), 7.01 (d, 1H, J¼8.3 Hz), 3.91 (s, 3H); dC (125 MHz,
CDCl3): 192.6, 158.1, 142.1, 141.6, 134.1, 133.1, 132.2,
132.1, 130.4, 129.7, 129.0, 127.5, 125.7, 124.4, 120.8,
111.6, 55.57; m/z (HR-ESI): theoretical mass (MþH)þ,
317.0099; found, 317.0231.
1
alumina column. H and 13C NMR spectra were recorded on
an Inova Instrument at 500 MHz (1H) and 125 MHz (13C).
11B and 19F NMR spectra were recorded on an Inova 400
Broad Band instrument at 128 MHz (11B) and 376 MHz
(19F). NMR chemical shifts are expressed in parts per million
relative to internal solvent peaks, and coupling constants were
measured in hertz. For 11B NMR, BF3$OEt2 has been used as
an external reference; similarly, CFCl3 was used as an external
standard for the 19F spectra.
4.1.1. 1-(4-Iodophenyl)-3-(4-methoxyphenyl)prop-2-en-1-
one (4a)41,42
4-Methoxybenzaldehyde (5.53 g, 0.04 mol), 4-iodoaceto-
phenone (10.00 g, 0.04 mol), and potassium hydroxide
(0.16 g, 4.06 mmol) were dissolved in methanol/H2O (1:1
v/v, 120 mL) and stirred under reflux for 12 h. During the
course of the reaction, the product precipitated from the reac-
tion mixture. After cooling, the reaction mixture was filtered
and washed with methanol to give the product as a white solid
(11.35 g, 77%), mp (uncorrected) 162.2e163.3 ꢂC. dH
(500 MHz, CDCl3): 7.84 (d, 2H, J¼8.1 Hz), 7.78 (d, 1H,
J¼15.6 Hz), 7.71 (d, 2H, J¼8.1 Hz), 7.59 (d, 2H, J¼8.3 Hz),
7.33 (d, 1H, J¼15.6 Hz), 6.93 (d, 2H, J¼8.3 Hz), 3.85 (s,
3H); dC (125 MHz, CDCl3): 189.6, 161.8, 145.2, 137.8,
137.7, 130.3, 129.8, 127.3, 118.9, 114.4, 100.3, 55.4; m/z
(ESI): theoretical mass (MþH)þ, 365.00; found, 365.01.
4.1.5. (E)-3-(4-Iodophenyl)-1-(2-methoxyphenyl)prop-2-en-
1-one (4e)
A solution of 2-methoxyacetophenone (1.43 g, 0.011 mol)
in ethanol (11 mL) was added gradually to an aqueous solution
of 10% KOH (32 mL) at 0 ꢂC. After stirring for 30 min,
4-iodobenzaldehyde (2.0 g, 0.009 mol) was added to the solu-
tion and stirred at 0 ꢂC for an additional 15 min. The reaction
mixture was then allowed to warm up to room temperature and
stirred for 12 h. The product precipitated from the reaction
mixture over the course of the reaction. It was filtered and
washed with water to afford the desired product as a white
solid (2.8 g, 85%). dH (500 MHz, CDCl3): 7.74 (d, 2H,
J¼8.3 Hz), 7.64 (dd, 1H, J¼7.6, 1.7 Hz), 7.56e7.37 (m,
3H), 7.32 (d, 2H, J¼8.3 Hz), 7.05 (td, 1H, J¼7.6, 1 Hz),
7.01 (d, 1H, J¼8.3 Hz), 3.91 (s, 3H); dC (125 MHz, CDCl3):
192.5, 158.1, 141.6, 138.0, 134.6, 133.1, 130.4, 129.8,
129.0, 127.8, 120.8, 111.6, 96.4, 55.7; m/z (HR-ESI): theoret-
ical mass (MþH)þ, 365.0038; found, 365.0098.
4.1.2. 3-(4-Bromophenyl)-1-(4-methoxyphenyl)prop-2-en-1-
one (4b)43
4-Bromobenzaldehyde (5.00 g, 0.027 mol), 4-methoxyace-
tophenone (3.22 g, 0.027 mol), and potassium hydroxide
(0.108 g, 2.7 mmol) were dissolved in ethanol (30 mL) and
stirred at room temperature for 12 h. The product, which pre-
cipitated upon formation was filtered and washed with ethanol
and water. The titled product was obtained as a white solid
(7.3 g, 85%), mp (uncorrected) 149e150 ꢂC. dH (500 MHz,
CDCl3): 8.04 (d, 2H, J¼8.8 Hz), 7.73 (d, 1H, J¼15.6 Hz),
7.49e7.55 (m, 5H), 6.99 (d, 2H, J¼8.8 Hz), 3.89 (s, 3H); dC
(125 MHz, CDCl3): 188.3, 163.5, 142.4, 133.9, 132.1, 130.8,
4.1.6. 3-(4-Bromophenyl)-1-(2,4-dimethoxyphenyl)prop-2-
en-1-one (4f)47
A solution of acetophenone (1.95 g, 0.011 mol) in ethanol
(11 mL) was added gradually to an aqueous solution of 10%

3650
A. Loudet et al. / Tetrahedron 64 (2008) 3642e3654
KOH (32 mL) at 0 ꢂC. After stirring for 30 min, 4-bromoben-
zaldehyde (2.00 g, 0.011 mol) was added to the solution and
stirred at 0 ꢂC for an additional 15 min. The reaction mixture
was then allowed to warm up to room temperature and stirred
for 12 h. The product precipitated from the reaction mixture
over the course of the reaction. It was filtered and washed
with water to afford the desired product as a white solid
(2.8 g, 73%). dH (500 MHz, CDCl3): 7.77 (d, 1H, J¼8.8 Hz),
7.44e7.62 (m, 6H), 6.57 (dd, 1H, J¼8.8, 2.4 Hz), 6.50 (d,
1H, J¼2.2 Hz), 3.88 (s, 3H), 3.91 (s, 3H); dC (125 MHz,
CDCl3): 190.0, 164.3, 160.4, 140.3, 134.4, 132.9, 131.9,
129.6, 127.7, 124.0, 121.9, 105.2, 98.6, 55.7, 55.5; m/z
(HR-ESI): theoretical mass (MþLi)þ, 353.0365; found,
353.0384e355.0366 (Br isotope).
standing overtime) in nearly quantitative yield. This product
was used in the next without further purification.
4.2.1. 1-(4-Iodophenyl)-3-(4-methoxyphenyl)-4-nitrobutan-
1-one (5a)
dH (500 MHz, CDCl3): 7.82 (d, 2H, J¼8.3 Hz), 7.61 (d, 2H,
J¼8.3 Hz), 7.18 (d, 2H, J¼8.8 Hz), 6.86 (d, 2H, J¼8.8 Hz),
4.78 (ddAB system, 1H, J¼12.5, 6.8 Hz), 4.64 (ddAB
,
system
1H, J¼12.5, 7.8 Hz), 4.15 (apparent quint, 1H, J¼7.1 Hz),
3.77 (s, 3H), 3.37 (ddAB system, 2H, J¼7.3, 1.2 Hz); dC
(125 MHz, CDCl3):196.3, 159.1, 138.0, 135.6, 130.7, 129.3,
128.4, 114.4, 101.6, 79.7, 55.2, 41.5, 38.5; m/z (APCI): theo-
retical mass (M)þ, 425.01; found, 425.1.
4.2.2. 3-(4-Bromophenyl)-1-(4-methoxyphenyl)-4-
nitrobutan-1-one (5b)
4.1.7. (E)-3-(4-Bromophenyl)-1-(4-(dimethylamino)-2-
methoxyphenyl)prop-2-en-1-one (4g)
dH (500 MHz, CDCl3): 7.89 (d, 2H, J¼8.8 Hz), 7.45 (d, 2H,
J¼8.5 Hz), 7.17 (d, 2H, J¼8.5 Hz), 6.93 (d, 2H, J¼8.8 Hz),
4.8 (ddAB system, 1H, J¼12.5, 6.1 Hz), 4.65 (ddAB system, 1H,
J¼12.5, 8.3 Hz), 4.19 (apparent quint, 1H, J¼7.1 Hz), 3.87
(s, 3H), 3.37 (2 coalesced ddAB system, 2H, J¼17.6, 6.6 Hz);
dC (125 MHz, CDCl3):194.9, 163.9, 138.2, 132.1, 130.3,
129.2, 129.2, 121.7, 113.9, 79.3, 55.5, 40.8, 38.8; m/z
(APCI): theoretical mass (M)þ, 377.02; found, 377.9e379.9
(Br isotope).
NaOH (776 mg, 19.4 mmol) was added to a solution of bro-
mobenzaldehyde (1.44 g, 7.8 mmol) and 1-(4-dimethylamino-
2-methoxyphenyl)ethanone (1.5 g, 7.8 mmol) in 20 mL
MeOH. The reaction mixture was stirred at room temperature
for 24 h. The solid was collected on a filter and washed with
cold MeOH to afford the title compound (2.5 g, 89%) as a light
yellow solid. dH (500 MHz, CDCl3): 7.81 (d, 1H, J¼8.9 Hz),
7.62 (m, 2H), 7.45 (m, 4H), 6.32 (dd, 1H, J¼8.9, 2.4 Hz),
6.09 (d, 1H, J¼2.4 Hz), 3.91 (s, 3H), 3.05 (s, 6H); dC
(125 MHz, CDCl3): 188.4, 161.3, 154.8, 139.0, 135.0, 133.3,
131.9, 129.5, 128.4, 123.5, 116.8, 104.7, 94.0, 55.5, 40.1; m/z
(HR-ESI): theoretical mass (MþLi)þ C18H18BrLiNO2,
366.0681; found, 366.0584.
4.2.3. 1-(2-Methoxyphenyl)-4-nitro-3-phenylbutan-1-one
(5c)45,46,49
dH (500 MHz, CDCl3): 7.62 (dd, 1H, J¼7.8, 1.9 Hz), 7.48
(td, 1H, J¼7.3, 1.9 Hz), 7.30e7.34 (m, 2H), 7.25e7.24 (m,
3H), 7.00e6.96 (m, 2H), 4.8 (ddAB system, 1H, J¼7.6,
1.2 Hz), 4.65 (ddAB system, 1H, J¼8.3, 1.2 Hz), 4.18 (apparent
quint, 1H, J¼7.1 Hz), 3.89 (s, 3H), 3.46 (ddAB system, 2H,
J¼2.9, 3.7 Hz); dC (125 MHz, CDCl3): 198.9, 158.6, 139.4,
134.0, 130.4, 128.8, 127.6, 127.5, 127.4, 120.8, 111.5, 79.9,
55.5, 46.7, 39.7; m/z (HR-ESI): theoretical mass (MþH)þ,
300.1236; found, 300.1237.
4.1.8. (E)-3-(4-Bromophenyl)-1-(4-iodophenyl)prop-2-en-1-
one (4h)48
4-Bromobenzaldehyde (20.0 g, 0.11 mol), 4-iodoacetophe-
none (26.6 g, 0.11 mol), and sodium hydroxide (0.432 g,
0.01 mol) were dissolved in a 1:1 mixture of methanol/water
(400 mL) and stirred under reflux for 12 h. After cooling to
room temperature, the product was filtered and washed with
methanol. The title product was obtained as a white solid
(42.7 g, 96%). dH (500 MHz, CDCl3): 7.88 (d, 2H,
J¼8.6 Hz), 7.75 (d, 2H, J¼15 Hz), 7.73 (d, 2H, J¼8.6 Hz),
7.51 (d, 2H, J¼8.6 Hz), 7.45 (d, 2H, J¼15 Hz); dC
(125 MHz, CDCl3): 189.4, 143.9, 137.9, 137.2, 133.6, 132.3,
129.9, 129.8, 125.1, 121.9, 100.8; m/z (APCI): theoretical
mass (M)þ, 411.9; found, 413.09.
4.2.4. 3-(4-Bromophenyl)-1-(2-methoxyphenyl)-4-
nitrobutan-1-one (5d)
dH (500 MHz, CDCl3): 7.64 (dd, 1H, J¼7.6, 1.7 Hz), 7.49
(td, 1H, J¼7.6, 1.7 Hz), 7.45 (d, 2H, J¼8.5 Hz), 7.14 (d,
2H, J¼8.5 Hz), 7.00e6.97 (m, 2H), 4.78 (ddAB system, 1H,
J¼12.5, 6.3 Hz), 4.62 (ddAB system, 1H, J¼12.5, 8.3 Hz),
4.16 (apparent quint, 1H, J¼6.8 Hz), 3.91 (s, 3H), 3.42 (dd,
2H, J¼6.8, 1.7 Hz); dC (125 MHz, CDCl3): 158.5, 138.4,
134.1, 131.8, 130.3, 129.2, 127.0, 121.3, 120.7, 111.4, 79.4,
55.3, 46.4, 39.0 (signal for CO missing); m/z (HR-ESI): theo-
retical mass (MþLi)þ, 384.0423; found, 384.0429e386.0451
(Br isotope).
4.2. General procedure for the synthesis of Michael adduct
5aeg
A solution of chalcone (1 mmol), nitromethane (20 mmol),
and KOH (0.2 mmol) in ethanol (1 mL) was heated at 60 ꢂC
for 12 h. After cooling to room temperature, the solvent was
removed in vacuo and the oily residue obtained was dissolved
in ethyl acetate and washed with water (3ꢃ50 mL). The com-
bined organic layers were washed with brine, dried over
sodium sulfate, and concentrated to give the target compound
as a yellow/off white solid or oily residue (that solidifies upon
4.2.5. 3-(4-Iodophenyl)-1-(2-methoxyphenyl)-4-nitrobutan-
1-one (5e)
dH (500 MHz, CDCl3): 7.66e7.63 (m, 3H), 7.50 (2 touch-
ing dd, 1H, J¼7.3, 1.9 Hz), 7.02 (d, 2H, J¼8.3 Hz), 6.98 (t,
2H, J¼8.3 Hz), 4.78 (m, 1H), 4.62 (m, 1H), 4.12 (m, 1H),
3.90 (s, 3H), 3.42 (m, 2H); dC (125 MHz, CDCl3): 158.6,

A. Loudet et al. / Tetrahedron 64 (2008) 3642e3654
3651
139.2, 137.9, 134.2, 130.5, 129.5, 127.1, 120.8, 111.5, 93.1,
79.5, 55.5, 46.5, 39.3 (C for carbonyl group not seen); m/z
(APCI): theoretical mass (M)þ, 425.01; found, 425.1.
crude product was used in the next step without any further
purification.
4.3.1. Azadipyrromethene 6a
4.2.6. 3-(4-Bromophenyl)-1-(2,4-dimethoxyphenyl)-4-
nitrobutan-1-one (5f)
dH (500 MHz, CDCl3): 7.70 (d, 4H, J¼7.8 Hz), 7.48 (d, 4H,
J¼8.3 Hz), 7.26 (d, 2H, J¼7.8 Hz), 7.04 (s, 2H), 6.92 (d, 4H,
J¼8.3 Hz), 6.77 (s, 2H), 3.96 (s, 6H); m/z (APCI): theoretical
mass (M)þ, 762.01; found, 762.10.
dH (500 MHz, CDCl3): 7.76 (d, 1H, J¼8.8 Hz), 7.44 (d, 2H,
J¼8.5 Hz), 7.14 (d, 2H, J¼8.5 Hz), 6.51 (dd, 1H, J¼8.8,
2.4 Hz), 6.45 (d, 1H, J¼2.2 Hz), 4.77 (ddAB system, 1H,
J¼12.4, 6.3 Hz), 4.61 (ddAB system, 1H, J¼12.4, 8.8 Hz),
4.13 (apparent quint, 1H, J¼7.1 Hz), 3.87 (s, 3H), 3.85 (s,
4.3.2. Azadipyrromethene 6b
m/z (HR-ESI): theoretical mass (MþH)þ, 666.0392; found,
666.0399e668.0366 (Br isotope). Attempt to take NMR in
CDCl3 only gave broad signals probably because of
aggregation.
3H), 3.39 (ddAB system, 1H, J¼17.6, 6.6 Hz), 3.34 (ddAB system
,
1H, J¼17.6, 7.6 Hz); d (125 MHz, CDCl3): 196.0, 164.9,
C
160.8, 138.8, 132.9, 131.9, 129.2, 121.4, 119.9, 105.4, 98.2,
79.6, 55.5, 55.4, 46.4, 39.2; m/z (HR-ESI): theoretical mass
(MþLi)þ, 414.0528; found, 414.0537e416.0497 (Br isotope).
4.3.3. Azadipyrromethene 6c
dH (500 MHz, CDCl3): 8.13 (d, 2H, J¼7.8 Hz), 8.07 (d, 4H,
J¼7.3 Hz), 7.44e7.33 (m, 10H), 7.08 (t, 2H, J¼7.3 Hz), 7.04
(d, 2H, J¼8.3 Hz), 3.96 (s, 6H); dC (125 MHz, CDCl3): 158.0,
153.5, 148.5, 141.0, 134.1, 130.9, 129.1, 128.1, 127.9, 127.5,
121.4, 121.0, 117.8, 111.8, 55.9; m/z (HR-ESI): theoretical
mass (MþH)þ, 510.2182; found, 510.2174.
4.2.7. 3-(4-Bromophenyl)-1-(4-(dimethylamino)-2-
methoxyphenyl)-4-nitrobutan-1-one (5g)
dH (500 MHz, CDCl3): 7.75 (d, 1H, J¼8.9 Hz), 7.41 (m,
2H), 7.13 (m, 2H), 6.26 (dd, 1H, J¼8.9, 2.3 Hz), 6.00 (d,
1H, J¼2.3 Hz), 4.78 (ddAB system, 1H, J¼12.7, 5.8 Hz), 4.58
(ddAB system, 1H, J¼12.7, 9.1 Hz), 4.12 (m, 1H), 3.86 (s,
3H), 3.34 (ddAB system, 1H, J¼17.0, 6.3 Hz), 3.26 (ddAB system
,
1H, J¼17.0, 8.0 Hz), 3.03 (s, 6H); d (125 MHz, CDCl3):
4.3.4. Azadipyrromethene 6d
C
194.7, 161.5, 155.1, 139.3, 132.8, 131.9, 129.3, 121.2,
114.8, 104.6, 93.3, 79.7, 55.1, 46.2, 40.1, 39.4; m/z (APCI):
theoretical mass (MþH)þ, 421.06; found, 421.14.
dH (500 MHz, CDCl3): 8.08 (d, 2H, J¼7.3 Hz), 7.87 (d, 4H,
J¼8.5 Hz), 7.51 (d, 4H, J¼8.8 Hz), 7.41 (dt, 2H, J¼7.3,
1.7 Hz), 7.28 (s, 2H), 7.09e7.02 (m, 4H), 3.95 (s, 6H); dC
(125 MHz, CDCl3): 157.9, 153.5, 148.2, 139.5, 132.9, 131.1,
130.4, 129.1, 121.7, 121.1, 121.0, 117.9, 117.8, 111.7, 55.9;
m/z (HR-ESI): theoretical mass (MþH)þ, 666.0392; found,
666.0399e668.0366 (Br isotope).
4.2.8. 2-(4-Bromophenyl)-4-(4-iodophenyl)-4-oxobutane-
nitrile (7)
Solution (6 mL) of 10% sodium carbonate was added to
a solution of (E)-3-(4-bromophenyl)-1-(4-iodophenyl)prop-2-
en-1-one 4h (1.0 g, 2.42 mmol) and acetone cyanohydrin
(0.5 g, 6.05 mmol) in acetone (20 mL). After refluxing for
12 h, the reaction mixture was allowed to cool to room temper-
ature. The content of the flask was poured into an Erlenmeyer,
and water was added to induce the separation of the product.
Compound 7 was obtained as a yellow powder in 75% yield
(0.805 g). dH (500 MHz, CDCl3): 7.82 (d, 2H, J¼8.6 Hz),
7.59 (d, 2H, J¼8.6 Hz), 7.50 (d, 2H, J¼8.3 Hz), 7.30 (d, 2H,
J¼8.3 Hz), 4.49 (apparent t, 1H, J¼7.6, 6.3 Hz), 3.65 (ddAB
system, 1H, J¼18.1, 7.6 Hz), 3.44 (ddAB system, 1H, J¼18.1,
6.3 Hz); dC (125 MHz, CDCl3): 193.7, 138.1, 134.5, 133.9,
132.3, 129.6, 129.2, 122.4, 119.9, 98.8, 43.9, 31.2; m/z
(APCI): theoretical mass (M)þ, 440.07; found, 440.08.
4.3.5. Azadipyrromethene 6e
dH (500 MHz, CDCl3): 8.09 (dd, 2H, J¼7.6, 1.7 Hz), 7.75
(apparent doublet of quart, 8H, J¼8.5, 2.2 Hz), 7.41 (dt, 2H,
J¼7.3, 1.7 Hz), 7.30 (s, 2H), 7.08 (dt, 2H, J¼7.6, 1.0 Hz),
7.04 (d, 2H, J¼8.5 Hz), 3.95 (s, 6H); dC (125 MHz, CDCl3):
158.1, 153.7, 148.4, 139.8, 137.3, 133.5, 131.3, 130.7,
129.2, 121.2, 121.1, 117.9, 111.8, 93.6, 55.9; m/z (APCI):
theoretical mass (M)þ, 762.01; found, 762.10.
4.3.6. Azadipyrromethene 6f
dH (500 MHz, CDCl3): 8.03 (d, 2H, J¼8.5 Hz), 7.88 (d, 4H,
J¼8.3 Hz), 7.51 (d, 4H, J¼8.3 Hz), 7.21 (s, 2H), 6.60 (dd, 2H,
J¼8.5, 2.4 Hz), 6.56 (d, 2H, J¼2.4 Hz), 3.95 (s, 6H), 3.90 (s,
6H); dC (125 MHz, CDCl3): 162.5, 159.4, 152.9, 148.1, 139.3,
133.2, 131.2, 130.5, 130.3, 121.6, 117.2, 114.5, 105.9, 98.8,
56.0, 55.6; m/z (HR-ESI): theoretical mass (MþH)þ,
726.0603; found, 726.0587e728.0555 (Br isotope).
4.3. General procedure for the synthesis of azadipyrro-
methene 6aeg
A 100 mL round-bottomed flask was charged with 5
(1 equiv), ammonium acetate (35 equiv), and butanol, and
heated under reflux for 24 h. After cooling to room tempera-
ture, the solvent was concentrated to a quarter of its original
volume, filtered, and the isolated solid was washed with etha-
nol to yield the desired product as a dark blue-black solid. The
4.3.7. Azadipyrromethene 6g
Not isolated, used in the next step without purification and
characterization; m/z (APCI): theoretical mass (MþH)þ,
752.12; found, 754.33.

3652
A. Loudet et al. / Tetrahedron 64 (2008) 3642e3654
4.3.8. Azadipyrromethene 6h
JBeF¼30 Hz); dF (376 MHz, CDCl3): ꢀ133.37 (q, 2F,
JBeF¼30 Hz). MS (HR-ESI) m/z calcd for (MþH)þ
A 100 mL round-bottomed flask was charged with 7 (3.0 g,
6.2 mmol), hydroxylamine hydrochloride (15.0 g, 217 mmol),
and methanol (30 mL) and heated at 100 ꢂC for 3 d. After
cooling to room temperature, the solvent was concentrated
to a quarter of its original volume, filtered, and the isolated
solid was washed with water then methanol to yield the de-
sired product as a light blue-green solid (1.68 g, 32%). dH
(500 MHz, CDCl3): 7.88 (d, 4H, J¼8.6 Hz), 7.72 (d, 4H,
J¼8.6 Hz), 7.64 (d, 4H, J¼8.6 Hz), 7.54 (d, 4H, J¼8.6 Hz),
7.49 (s, 2H), 3.96 (s, 6H); dC (125 MHz, CDCl3): 162.9,
154.2, 138.7, 135.4, 132.4, 131.3, 130.7, 130.5, 128.3,
126.1, 125.9, 98.3; m/z (APCI): theoretical mass (MþH)þ,
859.13; found, 859.98.
C34H27BF2N3O2, 558.2164; found, 558.2166; lmax
abs
(PhMe)/nm 640 (3¼73,858 dm3 molꢀ1 cmꢀ1); lmax
emis
(PhMe)/nm 688; F¼0.07 in 1% pyridine in toluene.
4.4.4. Aza-BODIPY 1d
dH (500 MHz, CDCl3): 7.90 (d, 4H, J¼8.8 Hz), 7.87 (dd,
2H, J¼7.6, 1.7 Hz), 7.60 (d, 4H, J¼8.8 Hz), 7.41 (dt, 2H,
J¼7.6, 1.7 Hz), 7.05e7.01 (m, 4H), 6.97 (d, 2H, J¼7.8 Hz),
3.86 (s, 6H); dC (125 MHz, CDCl3): 158.0, 157.0, 144.7,
141.4, 131.9, 131.8, 131.7, 131.4, 130.6, 123.7, 121.4,
120.7, 120.5, 111.0, 55.8; dB (128 MHz, CDCl3): 0.51 (t,
1B, JBeF¼30 Hz); dF (376 MHz, CDCl3): ꢀ137.46 (q, 2F,
JBeF¼30 Hz). MS (HR-MALDI) m/z calcd for (MþH)þ
C34H25BBr2F2N3O2, 714.0375; found, 714.0363e715.0370
4.4. General procedure for the synthesis of aza-BODIPY
1aeg
(Br
isotope);
lmax
(PhMe)/nm
650
(3¼
abs
55,014 dm3 molꢀ1 cmꢀ1); lmax emis (PhMe)/nm 694; F¼0.10
A flame dried Schlenk flask was charged with the azapyrro-
methene (1 equiv) and flushed with nitrogen. Dry dichlorome-
thane and dry diisopropylethylamine (11 equiv) were then
added. The solution was stirred at 25 ꢂC for 15 min, then dis-
tilled BF3$OEt2 (15.6 equiv) was added. After stirring at 25 ꢂC
for 24 h, the mixture was washed with water, and the organic
layer dried over sodium sulfate and concentrated in vacuo to
give the target compound.
in 1% pyridine in toluene.
4.4.5. Aza-BODIPY 1e
dH (500 MHz, CDCl3): 7.86 (dd, 2H, J¼7.8, 1.7 Hz), 7.79
(apparent quart, 8H, J¼8.3 Hz), 7.40 (td, 2H, J¼9, 1.7 Hz),
7.03 (td, 2H, J¼7.8, 1 Hz), 7.02 (s, 2H), 6.97 (d, 2H,
J¼8.3 Hz), 3.85 (s, 6H); dC (125 MHz, CDCl3): 158.3, 157.3,
141.9, 138.0, 132.3, 132.2, 131.9, 130.9, 121.7, 121.6, 121.0,
120.8, 111.3, 96.1, 56.2; dF (376 MHz, CDCl3): 45.45 (q, 2F,
J¼31.5 Hz). MS (HR-ESI) m/z calcd for (MþLi)þ
4.4.1. Aza-BODIPY 1a
dH (500 MHz, CDCl3): 8.04 (d, 4H, J¼8.8 Hz), 7.83 (d, 4H,
J¼8.5 Hz), 7.75 (d, 4H, J¼8.8 Hz), 7.00 (d, 4H, J¼8.5 Hz),
6.89 (s, 2H), 3.91 (s, 6H); dC (125 MHz, CDCl3): 161.1,
157.9, 145.6, 144.1, 137.8, 131.1, 130.9, 130.8, 125.1,
117.2, 114.3, 98.0, 55.4; dB (128 MHz, CDCl3): 0.84 (t, 1B,
JBeF¼31 Hz); dF (376 MHz, CDCl3): ꢀ134.89 (q, 2F,
JBeF¼31 Hz). MS (HR-maldi) m/z calcd for (MþH)þ
C34H24BI2F2N3O2, 816.0179; found, 816.0019; lmax
(PhMe)/nm 653 (3/dm3 molꢀ1 cmꢀ1 71,600); lmax
abs
emis
(PhMe)/nm 701; F¼0.10 in 1% pyridine in toluene.
4.4.6. Aza-BODIPY 1f
dH (500 MHz, CDCl3): 7.96 (d, 2H, J¼8.8 Hz), 7.90 (dd, 4H,
J¼1.8, 6.7 Hz), 7.58 (dd, 4H, J¼1.8, 6.7 Hz), 7.06 (s, 2H), 6.58
(dd, 2H, J¼8.8, 2.4 Hz), 6.51 (d, 2H, J¼2.4 Hz), 3.86 (s, 6H),
3.85 (s, 6H); dC (125 MHz, CDCl3): 163.1, 159.8, 155.9,
144.6, 140.6, 133.2, 131.7, 131.6, 130.5, 123.4, 121.5, 113.8,
104.8, 98.8, 55.8, 55.5; dB (128 MHz, CDCl3): 0.71 (t, 1B,
C34H25BI2F2N3O2, 810.0097; found, 810.0071; lmax
abs
(PhMe)/nm 680 (3/dm3 molꢀ1 cmꢀ1 108,996); lmax
emis
(PhMe)/nm 711; F¼0.18 in 1% pyridine in toluene.
4.4.2. Aza-BODIPY 1b
JBeF¼30 Hz); dF (376 MHz, CDCl3): ꢀ170.14 (q, 2F, JBeF¼
dH (500 MHz, CDCl3): 8.08 (d, 4H, J¼8.8 Hz), 7.91 (d, 4H,
J¼8.5 Hz), 7.60 (d, 4H, J¼8.5 Hz), 7.04 (s, 2H), 7.02 (d, 4H,
J¼8.8 Hz), 3.90 (s, 6H); dC not taken due to poor solubility of
compound; dB (128 MHz, CDCl3): 1.05 (t, 1B, JBeF¼32 Hz);
dF (376 MHz, CDCl3): ꢀ132.36 (q, 2F, JBeF¼32 Hz). MS
(HR-MALDI) m/z calcd for (M)þ C34H24BBr2F2N3O2,
30 Hz). MS (HR-ESI) m/z calcd for (MþH)þ
C36H29BBr2F2N3O4, 774.0586; found, 774.0573e776.0550
(Br isotope); lmax
(PhMe)/nm 692 (3/dm3 molꢀ1 cmꢀ1
abs
66,200); lmax emis (PhMe)/nm 738; F¼0.20 in 1% pyridine in
toluene.
715.0278; found, 715.0285; lmax
(PhMe)/nm 702
4.4.7. Aza-BODIPY 1g (from butyrophenone 5g)
abs
(3/dm3 molꢀ1 cmꢀ1 84,118); lmax emis (PhMe)/nm 731; F¼0.42
NH4OAc (17.4 g, 0.23 mol) was added to the solution of 5g
(2.73 g, 6.5 mmol) in 50 mL n-BuOH. The reaction mixture
was heated at reflux for 24 h. After cooling to room tempera-
ture, the solution was concentrated to half its original volume.
The solid was filtered and washed with cold EtOH to afford 6g
(1.0 g, 41%) as a green solid, which was used in the next step
without further purification. DIEA (1.8 mL, 10.3 mmol) was
added to the solution of 6g (970 mg, 1.3 mmol) in 30 mL
dry DCM. The solution was stirred at room temperature for
15 min and BF3$OEt2 (1.6 mL, 12.9 mmol) was added. After
in 1% pyridine in toluene.
4.4.3. Aza-BODIPY 1c
dH (500 MHz, CDCl3): 8.07e8.08 (m, 4H), 7.89 (dd, 2H,
J¼7.8, 1.7 Hz), 7.48e7.38 (m, 8H), 7.04 (dd, 2H, J¼15.1,
0.9 Hz), 7.03 (s, 2H), 6.97 (d, 2H, J¼8.3 Hz), 3.80 (s, 6H);
dC (125 MHz, CDCl3): 158.0, 156.7, 144.9, 142.8, 132.6,
131.7, 129.3, 129.2, 129.1, 128.5, 121.3, 121.1, 120.5,
111.1, 55.9; dB (128 MHz, CDCl3): 0.558 (t, 1B,

A. Loudet et al. / Tetrahedron 64 (2008) 3642e3654
3653
stirring at room temperature for 24 h, the mixture was washed
with water (1ꢃ30 mL) and brine (1ꢃ30 mL). The organic
layer was dried over Na2SO4 and concentrated under reduced
pressure. The crude product was purified by flash chromatog-
raphy on silica gel eluting with 2:3 EtOAc/hexane to afford 1g
(867 mg, 84%) as a purple solid. dH (500 MHz, CDCl3): 8.03
(d, 2H, J¼9.2 Hz), 7.90 (d, 4H, J¼8.5 Hz), 7.53 (d, 4H,
J¼8.5 Hz), 7.14 (s, 2H), 6.34 (d, 2H, J¼9.1 Hz), 6.13 (d,
2H, J¼2.3 Hz), 3.84 (s, 6H), 3.01 (s, 12H); dC (125 MHz,
CDCl3): 160.2, 154.5, 153.2, 144.4, 138.5, 133.4, 132.2,
131.4, 130.4, 122.6, 121.5, 109.3, 104.8, 94.8, 55.6, 40.1; dF
(376 MHz, CDCl3): 45.45 (q, 2F, J¼31.5 Hz). MS (HR-ESI)
m/z calcd for (MþH)þ C38H35BBr2F2N5O2, 800.1219; found,
4H, J¼2.2, 9.3 Hz), 6.49 (d, 4H, J¼2.2 Hz), 3.90 (s, 6H); dC
(125 MHz, CD3OD): 182.6, 173.2, 162.6, 160.3, 159.9,
148.3, 144.6, 142.3, 134.9, 133.7, 133.6, 132.8, 132.5,
132.2, 132.1, 131.4, 131.3, 126.6, 126.2, 125.1, 124.1,
119.4, 115.3, 114.8, 113.1, 104.4, 92.1, 91.4, 55.9; dB
(128 MHz, CD3OD): 5.34; dF (376 MHz, CD3OD): ꢀ187.46;
m/z (HR-MALDI) calcd for C78H46BF2N3O12, 1265.3143;
found, 1267.3880; lmax abs (50% EtOH/H2O)/nm 500 (fluores-
cein) and 698 (aza-BODIPY); lmax emis (50% EtOH/H2O)/nm
530 and 733 when excited at 498 nm; lmax emis (50% EtOH/
H2O)/nm 733 when excited at 690 nm.
4.4.10. Compound 10
800.1275; lmax
(PhMe)/nm 798 (3/dm3 molꢀ1 cmꢀ1
BBr3 (1.0 mol solution in hexane) (4.9 mmol, 1.9 mL) was
added to a solution of iodoaza-BODIPY 1a (0.49 mmol, 0.4 g)
in dry CH2Cl2 (200 mL) at 0 ꢂC and stirred at 25 ꢂC for 2 h.
Dichloromethane was removed, then a 1:1 mixture of
EtOAc/water (300 mL) was added. The organic layer was
separated, dried over anhydrous MgSO4, filtered, and finally
THF (10ꢃ50 mL) was used to dissolve sticky material during
filtration. The filtrate was concentrated and dried under
vacuum. The crude product was used in next step without
further purification.
NaH (60% suspension in paraffin oil) (4.9 mmol, 290 mg)
was added to a solution of the crude unprotected aza-BODIPY
[(49.0 mmol, 383 mg) (assumed quantity)] and methyl bro-
moacetate (1.86 mmol, 1.47 mL) in dry THF (150 mL). After
stirring for 12 h at 25 ꢂC, flash silica gel was added to quench
the NaH as well as to make slurry for column chromatography.
The solvents were removed and chromatographed (SiO2; 50%
hexanes/EtOAc) to afford 10 (79 mg) in 17% yield as dark
blue amorphous solid. Rf¼0.30 (50% hexanes/EtOAc); 1H
NMR (500 MHz, CDCl3): d 7.93 (d, 4H, J¼9.0 Hz), 7.77 (d,
4H, J¼9.0 Hz), 7.68 (d, 4H, J¼9.0 Hz), 6.92 (d, 4H,
J¼9.0 Hz), 6.82 (s, 2H), 4.66 (s, 2H), 3.85 (s, 6H); 13C
NMR (75 MHz, CDCl3): d 169.2, 159.2, 158.1, 143.7, 138.1,
131.1 (3C), 126.2, 117.7, 115.0, 98.4, 65.4, 52.6. MS
(HR-MALDI) m/z calcd for C38H28BF2I2N3O6, 925.0129;
found, 925.6324.
abs
68,610); lmax emis (PhMe)/nm 830; F¼0.07 in 1% pyridine
in toluene.
4.4.8. Compound 11
A flame dried Schlenk tube was charged with ethynyl fluo-
rescein diacetate 923,33 (0.24 g, 0.54 mmol), aza-BODIPY 1a
(0.2 g, 0.25 mmol), Pd(PPh3)4 (17 mg, 0.025 mmol), CuI
(2.4 mg, 0.012 mmol), THF (15 mL), and triethylamine
(0.4 mL, 2.5 mmol). The reaction mixture was deoxygenated
three times using the freeze-pump-thaw technique. It was
then stirred at room temperature for 28 h. The solvent was
then removed in vacuo, and the residue purified by flash chro-
matography (dry loading). The column was first eluted with
50% hexanes/CH2Cl2 to 100% CH2Cl2, then 2% ethyl ace-
tate/CH2Cl2 to get the mono-coupling product and finally
with 5% ethyl acetate/CH2Cl2 to get the bis-coupling product.
The bis-coupling product is coeluted with the ethynyl fluores-
cein bis acetate homo-coupling product and is obtained in
a pure form after a second flash chromatography eluted with
50% ethyl acetate/hexanes (107 mg, 30%). dH (500 MHz,
CDCl3): 8.18 (s, 2H), 8.10 (d, 4H, J¼8.1 Hz), 8.06 (d, 4H,
J¼8.3 Hz), 7.83 (d, 2H, J¼8.1 Hz), 7.66 (d, 4H, J¼8.3 Hz),
7.19 (d, 2H, J¼8.1 Hz), 7.11 (d, 4H, J¼2.2 Hz), 7.02e6.99
(m, 6H), 6.88e6.83 (m, 8H), 3.91 (s, 6H), 2.32 (s, 12H); dC
(125 MHz, CDCl3): 168.8, 168.2, 161.1, 157.7, 152.2, 152.1,
151.5, 145.9, 143.9, 138.3, 131.9 (2C), 130.9, 129.6, 128.9,
128.2, 126.6, 125.5, 125.1, 124.6, 124.2, 117.8, 117.6,
115.9, 114.2, 110.5, 91.7, 89.9, 81.8, 55.4, 21.1; dB
(128 MHz, CDCl3): 0.97 (t, 1B, JBeF¼31 Hz); dF (376 MHz,
CDCl3): ꢀ130.72 (q, 2F, JBeF¼31 Hz); m/z (HR-MALDI)
calcd for C86H54BF2N3O16 (MþH)þ, 1434.3643; found,
1434.3638.
4.4.11. Compound 12
Ethynyl fluorescein diacetate 9 (0.43 mmol, 0.187 g) was
added to a solution of aza-BODIPY 10 (0.085 mmol,
0.79 g), PdCl2(PPh3)2 (25 mol %, 15 mg), CuI (5 mol %,
1 mg), and Et3N (1 mL) in dry THF (30 mL). The resulting so-
lution was freeze thawed (ꢀ78 ꢂC) for three times (every time
purged with Ar). After stirring for 18 h at 40 ꢂC, the solvents
were removed and chromatographed (SiO2; 12% EtOAc/
CH2Cl2) to afford 12 (53 mg) in 40% yield as dark brown
solid. Rf¼0.30 (6% EtOAc/CH2Cl2); 1H NMR (500 MHz,
CDCl3): d 8.18 (s, 2H), 8.08 (d, 4H, J¼8.5 Hz), 8.02 (d, 4H,
J¼8.5 Hz), 7.84e7.80 (m, 2H), 7.65 (d, 4H, J¼8.5 Hz), 7.18
(d, 2H, J¼7.5 Hz), 7.13 (d, 4H, J¼2.0 Hz), 6.99e7.01 (m,
6H), 6.84e6.85 (m, 8H), 4.73 (s, 4H), 3.85 (s, 6H), 2.31 (s,
12H); 13C NMR (125 MHz, CDCl3): d 179.3, 169.1, 168.5,
159.45, 158.2, 152.5 (2C), 151.8, 146.2, 143.9, 138.7, 132.3,
132.1, 131.3, 129.3 (2C), 129.3, 128.5, 126.9, 126.4, 125.8,
4.4.9. Compound 2
A solution of 11 in a mixture of methanol and THF (1:1)
was treated with baked potassium carbonate. The reaction
mixture was stirred at room temperature for 2 h. When the
reaction was complete according to TLC, the solvent was
removed in vacuo to afford the pure product. dH (500 MHz,
CD3OD): 8.30 (d, 4H, J¼8.5 Hz), 8.18 (d, 2H, J¼1.7 Hz),
8.15 (d, 4H, J¼8.8 Hz), 7.72 (dd, 2H, J¼1.7, 7.8 Hz), 7.66
(d, 4H, J¼8.5 Hz), 7.26 (s, 2H), 7.24 (d, 2H, J¼7.8 Hz),
7.06 (d, 4H, J¼9.3 Hz), 7.05 (d, 4H, J¼8.8 Hz), 6.54 (dd,

3654
A. Loudet et al. / Tetrahedron 64 (2008) 3642e3654
17. Zhao, W.; Carreira, E. M. Angew. Chem., Int. Ed. 2005, 44, 1677e1679.
18. Zhao, W.; Carreira, E. M. Chem.dEur. J. 2006, 12, 7254e7263.
19. Loudet, A.; Bandichhor, R.; Burgess, K. Angew. Chem., Int. Ed.,
manuscript in preparation.
125.1, 124.6, 118.2, 116.3, 115.2, 110.8, 92.0, 90.4, 82.1, 65.5,
52.7, 21.4; IR (neat); n (cmꢀ1); 1684. MS (HR-MALDI) m/z
calcd for C90H58BF2N2O20, 1549.3637; found (MꢀF),
1530.1506.
20. McDonnell, S. O.; O’Shea, D. F. Org. Lett. 2006, 8, 3493e3496.
21. Burgess,K.;Burghart, A.;Chen, J.;Wan, C.-W. Proc. SPIE-Int. Soc. Opt.Eng.
2000, 3926, 95e105.
4.4.12. Compound 3
22. Burghart, A.; Thoresen, L. H.; Chen, J.; Burgess, K.; Bergstrom, F.;
¨
Solid TMSOK (0.37 mmol, 48 mg) was added to a solution
of compound 12 (0.031 mmol, 48 mg) in THF (20 mL). After
stirring for 2 h 30 min at 25 ꢂC, the reaction mixture was neu-
tralized with 2 N HCl (1 mL) and subsequently added water
(5 mL). After stirring for 5 min, THF was removed and aque-
Johansson, L. B.-A. Chem. Commun. 2000, 2203e2204.
23. Jiao, G.-S.; Thoresen, L. H.; Kim, T. G.; Haaland, W. C.; Gao, F.; Topp,
M. R.; Hochstrasser, R. M.; Metzker, M. L.; Burgess, K. Chem.dEur. J.
2006, 12, 7616e7626.
24. Gorman, A.; Killoran, J.; O’Shea, C.; Kenna, T.; Gallagher, W. M.;
O’Shea, D. F. J. Am. Chem. Soc. 2004, 126, 10619e10631.
25. Rio, G.; Masure, D. Bull. Soc. Chim. Fr. 1972, 4604e4610.
26. Miura, T.; Urano, Y.; Tanaka, K.; Nagano, T.; Ohkubo, K.; Fukuzumi, S.
J. Am. Chem. Soc. 2003, 125, 8666e8671.
i
ous layer was extracted with 25% PrOH in CH2Cl2 (pH¼
2e3). To obtain pure product in 90% yield (38 mg) solvents
were removed and dried under vacuum. MS (HR-MALDI) m/z
calcd for C80H46BF2N3O6, 1353.2939; found, 1354.10212
(MþH). Pure compound 3 (<1 mg) was dissolved in 1:1
(CH3CN/H2O) (2 mL) and subjected to reverse phase analytical
HPLC {C18, 5:95 (CH3CN/H2O) and 0.1% TFA,
tR¼16.5 min}.
27. Gabe, Y.; Urano, Y.; Kikuchi, K.; Kojima, H.; Nagano, T. J. Am. Chem.
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28. Ueno, T.; Urano, Y.; Setsukinai, K.-i.; Takakusa, H.; Kojima, H.; Kikuchi,
K.; Nagano, T. J. Am. Chem. Soc. 2004, 126, 14079e14085.
29. Urano, Y.; Kamiya, M.; Kanda, K.; Ueno, T.; Hirose, K.; Nagano, T.
J. Am. Chem. Soc. 2005, 127, 4888e4894.
30. Tanaka, K.; Miura, T.; Umezawa, N.; Urano, Y.; Kikuchi, K.; Higuchi, T.;
Nagano, T. J. Am. Chem. Soc. 2001, 123, 2530e2536.
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Supplementary data
General experimental conditions, characterization data for
compounds 1e12, and X-ray crystallography of 1a are pro-
vided. This material is available free of charge via the internet
at http://pubs.acs.org. Supplementary data associated with this
article can be found in the online version, at doi:10.1016/
j.tet.2008.01.117.
33. Jiao, G.-S.; Han, J. W.; Burgess, K. J. Org. Chem. 2003, 68, 8264e
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35. Cox, R. J.; Durston, J.; Roper, D. I. J. Chem. Soc., Perkin Trans. 1 2002,
1029e1035.
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