Synthesis of 3,8-Dichloro-6-ethyl-1,2,5,7-tetramethyl-BODIPY from an Asymmetric Dipyrroketone and Reactivity Studies at the 3,5,8-Positions

Article abstract of DOI:10.1002/chem.201406550

The asymmetric BODIPY 1a (BODIPY=4,4-difluoro-4-bora-3a,4a-diaza-s-indacene), containing two chloro substituents at the 3,8-positions and a reactive 5-methyl group, was synthesized from the asymmetric dipyrroketone 3, which was readily obtained from available pyrrole 2a. The reactivity of 3,8-dichloro-6-ethyl-1,2,5,7-tetramethyl-BODIPY 1a was investigated by using four types of reactions. This versatile BODIPY undergoes regioselective Pd⁰-catalyzed Stille coupling reactions and/or regioselective nucleophilic addition/elimination reactions, first at the 8-chloro and then at the 3-chloro group, using a variety of organostannanes and N-, O-, and S-centered nucleophiles. On the other hand, the more reactive 5-methyl group undergoes regioselective Knoevenagel condensation with an aryl aldehyde to produce a monostyryl-BODIPY, and oxidation with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) gives the corresponding 5-formyl-BODIPY. Investigation of the reactivity of asymmetric BODIPY 1a led to the preparation of a variety of functionalized BODIPYs with λ_max of absorption and emission in the ranges 487-587 and 521-617 nm, respectively. The longest absorbing/emitting compound was the monostyryl-BODIPY 16, and the largest Stokes shift (49 nm) and fluorescence quantum yield (0.94) were measured for 5-thienyl-8-phenoxy-BODIPY 15. The structural properties (including 16 X-ray structures) of the new series of BODIPYs were investigated.

Full text of DOI:10.1002/chem.201406550

DOI: 10.1002/chem.201406550
Full Paper
&
Asymmetric Synthesis
Synthesis of 3,8-Dichloro-6-ethyl-1,2,5,7-tetramethyl–BODIPY from
an Asymmetric Dipyrroketone and Reactivity Studies at the 3,5,8-
Positions**
Ning Zhao, M. GraÅa H. Vicente,* Frank R. Fronczek, and Kevin M. Smith[a]
Abstract: The asymmetric BODIPY 1a (BODIPY=4,4-di-
fluoro-4-bora-3a,4a-diaza-s-indacene), containing two chloro
substituents at the 3,8-positions and a reactive 5-methyl
group, was synthesized from the asymmetric dipyrroketone
3, which was readily obtained from available pyrrole 2a. The
reactivity of 3,8-dichloro-6-ethyl-1,2,5,7-tetramethyl-BODIPY
1a was investigated by using four types of reactions. This
versatile BODIPY undergoes regioselective Pd0-catalyzed
Stille coupling reactions and/or regioselective nucleophilic
addition/elimination reactions, first at the 8-chloro and then
at the 3-chloro group, using a variety of organostannanes
and N-, O-, and S-centered nucleophiles. On the other hand,
the more reactive 5-methyl group undergoes regioselective
Knoevenagel condensation with an aryl aldehyde to produce
a monostyryl-BODIPY, and oxidation with 2,3-dichloro-5,6-di-
cyano-1,4-benzoquinone (DDQ) gives the corresponding 5-
formyl-BODIPY. Investigation of the reactivity of asymmetric
BODIPY 1a led to the preparation of a variety of functional-
ized BODIPYs with lmax of absorption and emission in the
ranges 487–587 and 521–617 nm, respectively. The longest
absorbing/emitting compound was the monostyryl-BODIPY
16, and the largest Stokes shift (49 nm) and fluorescence
quantum yield (0.94) were measured for 5-thienyl-8-phen-
oxy-BODIPY 15. The structural properties (including 16 X-ray
structures) of the new series of BODIPYs were investigated.
a catalyst, followed by boron complexation.[12] Similarly, meso-
aryl BODIPYs can be prepared from the reaction of 2-ketopyr-
role[13] with an a-free pyrrole fragment.[14] Alternatively, the syn-
thesis of symmetric 8-functionalized BODIPYs has been report-
ed via a dipyrrothioketone[15] or dipyrroketone[16] intermediate;
this route offers expeditious access to 8-thio or 8-halo-BODI-
PYs, respectively.
Introduction
4,4-Difluoro-4-bora-3a,4a-diaza-s-indacene dyes, known generi-
cally as borondipyrromethenes or BODIPYs, are very versatile
compounds that have attracted much attention since they
were first reported in 1968.[1] Due to their remarkable proper-
ties, including high extinction coefficients, and generally high
fluorescence quantum yields, low molecular weights, and high
thermal and photochemical stabilities,[2] BODIPYs have been
actively investigated in protein[3] and DNA-labeling,[3a,4] drug
delivery,[3a,5] light-harvesting arrays,[6] fluorescent switches,[7]
and in medical imaging and theranostics.[8]
Using the above methods, a number of BODIPY platforms,
such as those in Figure 1, have been synthesized and their re-
activity investigated.[2] For example, the a-methyl groups on
BODIPY platform a undergo Knoevenagel condensations with
various aldehydes, to produce the corresponding styryl-BODI-
PYs that display significant redshifted absorption and emission
spectra.[17] On the other hand, BODIPY platform b bearing 3,5-
chloro groups undergoes milder Pd0-catalyzed cross-coupling
A traditional approach to the synthesis of BODIPY scaffolds
involves the condensation reaction between excess a-free pyr-
roles and aldehydes[9] in the presence of a Lewis acid, followed
by DDQ oxidation to dipyrromethene, and then boron com-
plexation, using boron trifluoride diethyl etherate under basic
conditions. Alternatively, a-free pyrroles react with acid chlor-
ides[10] or anhydrides[11] to directly yield dipyrromethenes. An-
other efficient methodology for the preparation of both sym-
metric and asymmetric meso-free BODIPYs is by condensation
of a 2-formylpyrrole with an a-free pyrrole by using POCl3 as
[a] N. Zhao, Prof. Dr. M. G. H. Vicente, Dr. F. R. Fronczek, Prof. Dr. K. M. Smith
Department of Chemistry, Louisiana State University
Baton Rouge, LA, 70803 (USA)
E-mail: vicente@lsu.edu
[**] BODIPY=4,4-Difluoro-4-bora-3a,4a-diaza-s-indacene.
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201406550.
Figure 1. Examples of reported BODIPY platforms.
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reactions and nucleophilic substitution reactions at these posi-
tions, producing a variety of functionalized BODIPYs for various
applications.[18] Functionalizations at the 8-position of BODIPYs
are reported for platform c,[15,19] which undergoes nucleophilic
addition/elimination and Liebeskind–Srogl cross-coupling reac-
tions, and also for platform d bearing an 8-chloro group.[16]
Compared with the 8-methylthio-BODIPY c, platform d is more
versatile, reacting with a variety of N-, O-, and S-centered nu-
cleophiles, as well as under a variety of Pd0-catalyzed Stille,
Suzuki, and Sonogashira coupling conditions, producing the
corresponding functionalized BODIPYs in good to quantitative
yields.
We have recently synthesized a symmetric 3,5,8-trichloro-
BODIPY dye and explored its regioselectivity in Stille cross-cou-
pling conditions.[20] Herein we report the synthesis of a versa-
tile, asymmetric BODIPY 1a bearing two chloro substituents at
positions 3 and 8, as well as a reactive 5-methyl group, starting
from an asymmetric dipyrroketone. We show that BODIPY 1a
can be regioselectively functionalized using four types of reac-
tions, at positions 3, 5 and 8, to produce new conjugated BOD-
IPYs. The nucleophilic addition/elimination and cross-coupling
reactions both occur regioselectively at the 8-chloro followed
by the 3-chloro position, allowing stepwise functionalization
using various organometallic reagents and N-, O-, and S-cen-
tered nucleophiles. This is the first report on the meso- versus
a-position regioselectivity of BODIPY nucleophilic reactions.
Furthermore, the 5-methyl group undergoes regioselective
Knoevenagel and oxidation reactions, providing access to addi-
tional functionalized BODIPY platforms. The structural and
spectroscopic properties of the new BODIPYs were investigat-
ed.
Scheme 1. Synthesis of asymmetric 3,8-dichloro-BODIPY 1a.
propylethylamine (DIEA) produced BODIPY 1a in 78% overall
yield. The trans-chlorination of the 1-iododipyrroketone has
been previously observed under these reaction conditions;[20]
in addition, the 8-monochloro-BODIPY 1b was obtained as
a minor product from the reaction, in 6% yield.
The structures of BODIPYs 1a,b, dipyrroketones 3 and 5 and
1
Results and Discussion
dipyrrin 4 were confirmed by H, 13C NMR spectroscopy, HRMS
(ESI-TOF) and, in the case of 1a,b, 3, and 4 also by X-ray crys-
tallography (Figure 2). The structure of 1a has two independ-
ent molecules and a disordered chloroform solvent molecule.
The two molecules are almost identical with mean deviations
from planarity of their 12-atom BODIPY cores of 0.027 and
0.036 ꢁ, and a 9.88 torsional difference in the conformation of
the ethyl group. BODIPY 1b has four independent molecules,
and mean deviations of their BODIPY cores are in the range of
0.023–0.054 ꢁ. As in BODIPY 1a, the conformations of the
ethyl groups are essentially perpendicular to the BODIPY
planes, with C-C-C-C torsion angles differing from 908 by 0.3–
1.78.
The conformation of dipyrroketone 3 is such that one pyr-
role NH group is syn to the central carbonyl (N-C-C-O torsion
angle 15.58), while the other is syn to the benzyl ester carbonyl
(torsion angle 6.08). Both form intermolecular hydrogen bond
dimers. On the other hand, dipyrrin 4 is the hydrochloride salt,
with both N atoms protonated, forming hydrogen bonds to
the chloride. The C9N2 dipyrryl group is planar to within
a mean deviation of 0.017 ꢁ.
Synthesis and structural characterization
The synthetic route to asymmetric 3,8-dichloro-BODIPY 1a is
outlined in Scheme 1. The conversion of the a-methyl group
of readily available pyrrole 2a[21] to a carboxylic acid produced
2b,[22] which was acylated with thionyl chloride followed by re-
action with dimethylamine gas[22b] affording 5-(N,N-dimethyl-
amido)pyrrole 2c in 85% yield. The asymmetric dipyrroketone
3 was prepared by reaction of pyrrole 2c with phosphoryl
chloride, followed by addition of commercially available 3-
ethyl-2,4-dimethylpyrrole and subsequent hydrolysis using
aqueous sodium acetate[23] in 86% overall yield. When excess
phosgene was used to convert dipyrroketone 3 to the corre-
sponding 5-chlorodipyrrin salt, the dipyrryl salt 4 was obtained
instead by chlorination of the the a-methyl group of 3, proba-
bly due to the presence of the electron-withdrawing benzyl
ester.[20] Therefore, the benzyl ester was converted to an iodide
by debenzylation followed by decarboxylative iodination[24]
producing dipyrroketone 5 in 84% overall yield. The reaction
of 5 with excess phosgene (15% in toluene) was accompanied
by a color change from yellow to dark red, along with a down-
Previous work has shown that symmetric 8-chloro-,[16] 3,5-di-
chloro-[18c,d], and 3,5,8-trichloro-BODIPYs[20] undergo Pd0-cata-
lyzed cross-coupling reactions, including Suzuki, Sonogashira,
1
field shift of the NH protons in the H NMR spectrum. Subse-
quent boron complexation using excess BF3·OEt2 and N,N-diiso-
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the most reactive 8-chloride
when only one equivalent of or-
ganotin was used in a twice di-
luted solution (ca. 10ꢀ3 m) to pro-
duce BODIPYs 7a–c in 77–84%
yields.
The regioselectivity of these
Stille reactions was confirmed by
X-ray crystallography, as shown
in Figure 3. Crystals of BODIPYs
6a–c and 7c were grown from
slow diffusion of hexane into
a solution of BODIPY in dichloro-
methane. Except for BODIPY 7c,
all structures exhibit disorder,
with the thiophene at the 8-po-
sition in 6a having two confor-
mations, as do both furans in 6b
and the ethyl group in 6c. Mean
deviations from planarity of the
C9BN2 BODIPY cores are 0.072 ꢁ
for 6a, 0.087 for 6b, 0.054 for
6c, and 0.013 ꢁ for 7c. The sub-
stituents at the 8-positions devi-
ate by varying amounts from
Figure 2. X-ray crystal structures of BODIPYs 1a,b dipyrroketone 3 and dipyrryl salt 4 with 50% probability ellip-
soids. Only one of the independent molecules is shown for both 1a and 1b.
Heck, and Stille reactions to produce the corresponding aryl-,
alkyl-, alkenyl- and alkynyl-BODIPYs. Among these, the mild
Stille cross-couplings generally give high yields of the targeted
functionalized BODIPYs. Under similar conditions, BODIPY 1a
reacted in the presence of one or three equivalents of aryltin
reagent and 10 mol% of [Pd(PPh3)4] in toluene, to produce the
corresponding 8-aryl-3-chloro- and 3,8-diaryl-BODIPYs, as
shown in Scheme 2. The 3,8-diaryl-BODIPYs 6a–c were pro-
duced in 63–86% yields when an excess of organotin reagent
was used, whereas the reaction occurred regioselectively at
being perpendicular to the BODIPY cores, forming dihedral
angles of 87.78 for 6a, 83.08 for 6b, 79.78 for 6c, and 75.68 for
7c, to minimize steric interactions with the 1,7-methyl groups.
On the other hand, the aryl substituents at the 3-position devi-
ate much more from orthogonality with the BODIPY core,
forming dihedral angles of 41.78 for the thiophene in 6a, 36.98
for the furan in 6b, and 42.78 for the phenyl group in 6c.
We took advantage of the regioselectivity observed in the
Stille cross-coupling reactions to prepare BODIPYs 8–10 con-
taining two different aryl groups at the 3- and 8-positions, by
performing two consecutive Stille couplings using two differ-
ent organotin reagents (Scheme 3). Therefore, BODIPY 1a re-
acted with one equivalent of either 2-(tributylstannyl)thio-
phene or 2-(tributylstannyl)furan under Stille conditions to pro-
Scheme 2. Global and regioselective Stille coupling reactions of 3,8-dichloro-
BODIPY 1a.
Scheme 3. Sucessive Stille coupling reactions of 3,8-dichloro-BODIPY 1a.
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BODIPYs,[18a,b] although the re-
gioselectivity (i.e. meso vs. a-pyr-
rolic position) of these reactions
has never been investigated.
BODIPY 1a reacted at room tem-
perature, in the presence of po-
tassium carbonate, with up to
10 equivalents of either phenol
or aniline as the nucleophile, re-
gioselectively affording the 3-
chloro-BODIPYs 11 and 12, re-
spectively, in high yields (87–
95%). Similar conditions but
using p-methylthiophenol as the
nucleophile produced both the
mono- and disubstituted prod-
ucts, showing the higher reactiv-
ity of the sulphur-centered nu-
cleophile in these reactions.
When 10 equivalents of p-meth-
ylthiophenol were used, the dis-
ubstituted product 13 was the
major product, isolated in 93%
yield. With 1.5 equivalents of
thiol, the nucleophilic substitu-
tion reaction proceeded with re-
gioselectivity at only the meso-
position. These results illustrate
the higher reactivity of the 8-
Figure 3. X-ray crystal structures of asymmetric BODIPY dyes 6a–c and 7c (50% probability ellipsoids). Only the
major conformer is shown for disordered groups.
duce the 3-monochloro-BODIPYs 7a and 7b respectively;
these BODIPYs were subjected to a second Stille coupling with
a different organotin producing BODIPYs 8–10 in 58–91%
yields. While BODIPY 7a bearing a 8-thienyl group readily re-
acted with 2-(tributylstannyl)furan producing 8 in high yield,
BODIPY 7b reacted slower and required three equivalents of
organotin and a more concentrated reaction mixture (ca.
10ꢀ2 m) to produce BODIPYs 9 and 10 in moderate to high
yields.
Crystals suitable for X-ray analysis were obtained for all
three BODIPYs 8–10 and their structures are shown in Figure 4.
In BODIPY 8, both the furan and thiophene rings exhibit rota-
tional disorder. In these three structures, the planarity of the
BODIPY core and the dihedral angles formed by the planar
substituents at the 3- and 8-positions closely resemble the fea-
tures in compounds 6a–c and 7c. Mean deviations for the
C9BN2 cores are 0.082 ꢁ for 8, 0.071 ꢁ for 9, and 0.018 ꢁ for 10.
In BODIPY 8, the thiophene at the 8-position forms an 87.28
angle with the core, and the 8-furyl groups form slightly lower
corresponding dihedral angles of 84.88 in 9 and 78.08 in 10.
On the other hand the 3-furyl forms a dihedral angle of 38.68
with the BODIPY core plane in 8, and the 3-thienyl forms an
angle of 39.68 in 9.
Scheme 4. Nucleophilic additions/eliminations of BODIPY 1a.
chloro versus the 3-chloro group towards nucleophilic reac-
tions.
X-ray crystallography confirmed the regioselectivity of these
reactions; Figure 5 shows the structures of BODIPYs 11 and 12.
In both, there is a disorder in which the methyl and chloro
substituents at the 3- and 5-positions are swapped, the minor
component being present with about 8% population in both
Nucleophilic addition/elimination reactions of BODIPY 1a
were also investigated using N-, O-, and S-centered nucleo-
philes, as shown in Scheme 4. Such reactions have been previ-
ously reported on 8-chloro-BODIPYs,[16a,b] and on 3,5-dichloro-
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more, we anticipated that this
methyl group could be regiose-
lectively oxidized under mild
conditions, providing functionali-
ty for further derivatization and/
or conjugation of the BODIPY.[25]
To illustrate these reactions,
BODIPY 6c reacted with 4-for-
mylanisole in the presence of p-
toluenesulfonic acid and piperi-
dine, in refluxing toluene for
72 h, regioselectively affording
monostyryl-BODIPY 16 in 52%
yield (Scheme 6). The monostyr-
yl-BODIPY displays further red-
shifted absorbance and emission
spectra (see below, Table 1 and
Figure 7) and potential applica-
tions as a fluorescent sensor and
photosensitizer.[17]
The 3-methyl group of
BODIPY 6c was also regioselec-
tively oxidized in the presence
of DDQ[26] giving formyl-BODIPY
17 in 26% yield. Formyl-BODIPYs
are useful materials with poten-
tial applications as fluorescent
sensors,[27] and have been shown
to undergo Wittig reactions with
alkyl or aryl ylides,[28a] as well as
condensations with malononi-
trile, methyl acetoacetate,[28b]
and pyrrole[28c] to produce fur-
Figure 4. X-ray crystal structures of asymmetric BODIPY dyes 8–10 (50% probability ellipsoids). Only the main con-
formers are shown for the disordered thiophene and furan in 8.
cases. Mean deviations from coplanarity of the C9BN2 core
atoms are 0.033 ꢁ for 11 and 0.061 ꢁ for 12. Interestingly, the
plane of the 8-phenoxy group forms a dihedral angle of 86.78
with the BODIPY core in 11, whereas the aniline plane forms
an angle of 68.68 with the core in 12.
ther functionalized compounds.
BODIPYs 16 and 17 were characterized by X-ray crystallogra-
phy, as shown in Figure 6. BODIPY 16 crystallizes with two in-
Additionally, we investigated sucessive Stille cross-coupling
followed by nucleophilic substitution reactions, and vice-versa,
of BODIPY 1a, as shown in Scheme 5. Using this approach and
using similar conditions as described above for the two types
of reactions, BODIPYs 14 and 15 were synthesized in 67 and
91% overall yields, respectively. The first reaction always
occurs regioselectively at the most reactive 8-chloro, followed
by the second reaction at the 3-chloro group.
The X-ray structure for BODIPY 14 was also obtained to con-
firm the regioselectivity of these reactions, and it is shown in
Figure 5. The BODIPY core atoms are coplanar to within
a mean deviation of 0.019 ꢁ, and it forms a dihedral angle of
77.98 with the 8-phenyl group plane.
The 5-methyl group of BODIPY 1a was unreactive under the
Stille cross-coupling and nucleophilic addition/elimination re-
actions described above. However, it is known that the a-
methyl groups of BODIPYs can react with aldehydes under
Knoevenagel condensation conditions,[17] providing an addi-
tional reactive site for functionalization of BODIPY 1a. Further-
Scheme 5. Sucessive Stille cross-coupling and nucleophilic reactions of
BODIPY 1a.
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styryl group forms angles of 26.2
and 22.78 with the BODIPY core.
In BODIPY 17, the core atoms
have mean deviation of 0.075 ꢁ
from coplanarity, the 8-phenyl
group forms a dihedral angle of
72.78 with the BODIPY core and
the formyl CꢀC=O group forms
a small dihedral angle of 6.28
with the BODIPY core.
Spectroscopic properties
The spectroscopic properties of
BODIPYs 1, 6a–c, 7a–c, and 8–
17 in dichloromethane, namely
their maximum absorption and
fluorescence
wavelengths,
Stokes shifts, molar extinction
coefficients and fluorescence
quantum yields, are summarized
in Table 1. Figure 7 shows the
normalized absorption and fluo-
rescence spectra of four repre-
sentative BODIPYs (see the Sup-
porting Information for addition-
al BODIPY spectra). The BODIPYs
have characteristic absorption
and emission spectra, showing
Figure 5. X-ray crystal structures of asymmetric BODIPYS 11, 12, and 14 (50% probability ellipsoids). The disorder
in 11 and 12 is not shown.
dependent molecules in the asymmetric unit, and 17 as the
chloroform solvate. In 16, the BODIPY core atoms of the two
molecules have mean deviations of 0.064 and 0.078 ꢁ from co-
planarity. The 8-phenyl group forms dihedral angles of 84.0
and 75.08 with the BODIPY core, the 3-phenyl group forms di-
hedral angles of 59.8 and 65.98 with the BODIPY core, and the
high molar absorption coefficients (loge=4.22–4.95) and
Stokes-shifted fluorescence emission bands. Relative to BODIPY
Table 1. Spectroscopic properties of BODIPYs 1a,b, 6a–c, 7a–c, and 8–
17 in dichloromethane at room temperature.[a]
BODIPY Absorption log
Emission Ff
lmax [nm]
Stokes shift
[nm]
lmax [nm]
e [mꢀ1 cmꢀ1
]
1a
1b
6a
6b
6c
7a
7b
7c
8
517
513
547
586
523
529
535
515
577
556
563
505
487
582
512
521
587
538
4.80
4.95
4.64
4.78
4.71
4.73
4.78
4.71
4.53
4.66
4.84
4.52
4.52
4.35
4.41
4.62
4.22
4.46
540
536
591
611
551
548
555
536
592
577
582
521
531
610
532
570
617
562
0.52
0.33
0.097
0.022
0.46
0.09
0.0097
0.48
0.097
0.011
0.022
0.89
0.0017
0.13
23
23
44
25
28
19
20
21
15
21
19
16
44
28
20
49
30
24
9
10
11
12
13
14
15
16
17
0.41
0.94
0.73
0.24
[a] For BODIPYs 1a,b, 6c, 7a, 7c, 11, 12, 14, and 15 the calculation of
fluorescence quantum yield used rhodamine 6G in ethanol (0.95) as stan-
dard; for BODIPYs 6a, 7b, and 17, rhodamine B in ethanol (0.49) was
used as a standard; for BODIPYs 6b, 8–10, 13, and 16, crystal violet per-
chlorate in methanol (0.54) was used as standard.
Scheme 6. Knoevenagel and oxidation reactions of BODIPY 6c.
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The introduction of 8-thienyl
and 8-furyl groups into the
BODIPY core caused redshifts in
the absorption and emission
bands relative to BODIPY 1a,
particularly for the furan group,
due to a decrease in the HOMO–
LUMO gap. The largest redshifts
in the 3,8-diaryl-BODIPYs were
induced by furan groups at the
3-position, as in BODIPYs 6b and
8. However, these compounds
show low fluorescence quantum
yields (Ff <0.1), as a result of
the greater freedom of rotation
of the thienyl and furyl groups
in comparison with phenyl,
which increases the amount of
energy lost to nonradiative
decay to the ground state.[20,31]
Figure 6. X-ray crystal structures of asymmetric BODIPYS 16 and 17 (50% probability ellipsoids). Only one of the
two independent molecules of 16 is shown.
The monostyryl-BODIPY 16 showed the most redshifted fluo-
rescence emission (lmax =617 nm) of all the BODIPYs investi-
gated, and a high quantum yield (Ff =0.73). On the other
hand, the significant redshift in the absorption and emission of
formyl-BODIPY 17 relative to 6c is due to the conjugation of
the carbonyl group with the BODIPY p-system, as indicated by
the nearly co-planarity seen in the X-ray structure (Figure 6).
The lower quantum yield determined for 17 relative to 6c is in
agreement with previous reports.[26]
The Stokes shifts of the 3-, 5-, and/or 8-substituted BODIPYs
were generally larger than that of the starting BODIPY 1a, and
they were the largest for the 5-thienyl-BODIPYs 6a and 15 (44
and 49 nm, respectively), in agreement with previous studies,
probably due to increased geometry relaxation upon photoex-
citation of these compounds.[20,32] The 8-phenylamino-BODIPY
12 also showed larger Stokes shift (44 nm) than other function-
alized BODIPYs, in agreement with previous investigations.[29]
Figure 7. Normalized UV/Vis and fluorescence spectra of BODIPYs 6c (dash),
9 (dot), 11 (solid) and 16 (dash dot) in dichloromethane at room tempera-
ture.
1a bearing 3,8-chloro groups, slight blueshifts (1–5 nm) were
observed in the absorption and emission bands of BODIPYs 7c
and 14 bearing 8-phenyl groups, due to the large dihedral
angles between this group and the BODIPY core (see Figures 3
and 5) as a result of 1,7-dimethyl substitution.[20] Larger blue-
shifts were observed as a result from 8-phenoxy and 8-phenyl-
amino substitution, as previously observed for 8-aryloxy and 8-
arylamino-BODIPYs.[16,29] This is in part due to the destabiliza-
tion of the LUMO as a result of the electron-donating effect of
these groups, which increases the HOMO–LUMO gap. However
in contrast, the 8-phenoxy-BODIPY 11 showed a high fluores-
cence quantum yield (Ff =0.89), whereas the 8-phenylamino
analogue 12 was practically nonfluorescent (Ff <0.002), proba-
bly due to intramolecular charge transfer in the excited state.
The largest quantum yield was observed for the 8-phenoxy-
BODIPY 15, bearing a 5-thienyl group (Ff =0.94). On the other
hand, substitution at the 8-position with an arylthio group, as
in BODIPY 13, induced a low quantum yield (Ff =0.13), as pre-
viously observed.[16,29,30]
Conclusion
The total synthesis of 3,8-dichloro-6-ethyl-1,2,5,7-tetramethyl-
BODIPY 1a from an unsymmetric dipyrroketone was accom-
plished in good yield. BODIPY 1a undergoes four types of re-
actions: nucleophilic addition/elimination using N-, O-, and S-
centered nucleophiles and Stille cross-coupling reactions at the
3- and 8-chloro groups, as well as Knoevenagel condensation
and oxidation at the most reactive 5-methyl group. Excellent
selectivity for the meso-8- over the 3-chloro group of 1a was
observed using both nucleophilic and Stille coupling reactions.
This regioselectivity is likely the result of the higher electrophi-
licity of the meso-position versus the a-pyrrolic position based
on consideration of mesomeric resonance structures, and of
the different mechanistic pathways: SNAr for a-pyrrolic and ad-
dition/elimination for the meso-position. X-ray crystallography
(16 structures were obtained) was used to confirm the regiose-
lectivity of the reactions.
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ing solution was stirred overnight at room temperature. The reac-
tion was stopped when the signals for RCH2Cl (d=4.6 ppm) and
CHCl2 (d=6.7 ppm) disappeared from the 1H NMR spectra mea-
sured in CCl4. Organic solvents were removed under reduced pres-
sure to give a red oil residue. The oil residue was dissolved in diox-
ane (70 mL) and a solution of sodium acetate (11 g) in water
(60 mL) was added. The solution was stirred at 60–658C for 3 h.
The solution was then cooled to room temperature and extracted
using diethyl ether (2ꢂ70 mL). The organic layers were combined
and washed with 5% Na2CO3 aqueous solution. All the aqueous
layers were then combined and acidified by slowly adding acetic
acid (10%). A white precipitate was filtered and washed thorough-
ly with water. The solid was redissovled in THF and dried over an-
hydrous Na2SO4. The organic solvents were removed under re-
duced pressure to give the title product (3.64 g) in 74.7% yield.
1H NMR (CDCl3, 400 MHz): d=9.48 (1H, s), 7.40–7.44 (5H, m), 5.36
(2H, s), 2.30 ppm (6H, s); 13C NMR (CDCl3, 100 MHz): d=165.7,
160.7, 135.7, 129.2, 128.7, 128.4, 128.3, 127.7, 122.5, 120.8, 66.5,
10.1 ppm; MS (ESI-TOF) m/z: calcd for C15H16NO4: 274.1074; found:
274.1076 [M+H]+.
The BODIPYs with 8-phenyl, 8-phenoxy, and 8-phenylamino
groups showed blueshifted absorption and emission bands rel-
ative to BODIPY 1a. All other BODIPYs displayed redshifted
bands, with the monostyryl-BODIPY 16 showing the most red-
shifted absorption and emission of all BODIPYs. The Stokes
shifts varied between 15–49 nm, with the 5-thienyl-8-phenoxy-
BODIPY 15 showing the largest Stokes shift, and also the high-
est fluorescence quantum yield. In contrast to the phenyl- and
phenoxy-substitued BODIPYs, the compounds bearing phenyl-
amino, methylphenylthio, thienyl, and furyl groups at the 8-po-
sition of the BODIPY core showed very low fluorescence.
Experimental Section
Syntheses
General: All reagents and solvents were purchased from Sigma–Al-
drich, Fisher Scientific or Alfa Aesar as reagent grade and used
without further purification. Argon was used to protect the air-sen-
sitive reactions. Analytical TLC (polyester backed, 60 ꢁ, 0.2 mm,
precoated, Sorbent Technologies) was used to monitor the reac-
tions. Column chromatography was performed on silica gel (60 ꢁ,
Benzyl 5-N,N-dimethylamido-3,4-dimethylpyrrole-2-carboxyl-
ate (2c)
1
230–400 mesh, Sorbent Technologies). All H and 13C NMR spectra
5-Benzyloxycarbonyl-3,4-dimethylpyrrole-2-carboxylic acid (2b)
(4.6 g, 16.8 mol) was added portionwise into thionyl chloride
(65 mL) over 20 min. The mixture was stirred for 30 min at 40–
458C. The solvent was removed under reduced pressure to give an
oily product. The oily residue was redissolved in anhydrous ben-
zene (130 mL). Then, dimethylamine gas was passed into the mix-
ture for 10 min, and the mixture was stirred for another 2 h. The re-
action was monitored by TLC analysis. After the reaction was com-
pleted, the organic solution was washed with water (100 mL),
dilute acetic acid (10%), and water again (100 mL), and then dried
over anhydrous Na2SO4. The organic solvents were removed under
reduced pressure to give a yellow oil. Purification by silica gel
column chromatography with CH2Cl2/MeOH as the eluent gave the
were obtained using Bruker AV-400 nanobay or AV-500 spectrome-
ters (400 or 500 MHz for 1H and 100 MHz for 13C NMR, and
128 MHz for 11B NMR spectra) in CDCl3 with tetramethylsilane as an
internal standard, at room temperature. Chemical shifts (d) are
given in parts per million (ppm) versus CDCl3 (7.27 ppm for
1H NMR, 77.0 ppm for 13C NMR). All high-resolution mass spectra
(ESI-TOF) were obtained using a 6210 ESI-TOF mass spectrometer
(Agilent Technologies). All UV/Vis spectra were recorded on
a Varian Cary 50 spectrophotometer at room temperature. Fluores-
cence spectra were studied on a PTI QuantaMaster4/2006SE spec-
trofluorimeter with the slit width set at 3 nm at room temperature.
A 10 mm path length quartz cuvette and spectroscopic grade sol-
vents were used for the measurements. The determination of opti-
cal density (e) was used for the solutions with an absorbance of
lmax between 0.5–1. The dilute solutions with absorbance of partic-
ular excitation wavelength between 0.02–0.05 were used for fluo-
rescence quantum yield measurements. Rhodamine 6G (0.95 in
ethanol), rhodamine B (0.49 in ethanol) and crystal violet perchlo-
rate (0.54 in methanol) were used as external standards for calcula-
tion of the relative fluorescence quantum yields of the BODIPYs.
All fluorescence quantum yields (Ff) were determined using the
following equation:[33]
1
yellow titled product (4.3 g, 85.1%). H NMR: (CDCl3, 400 MHz): d=
9.05 (1H, s), 7.34–7.42 (5H, m), 5.31 (2H, s), 3.06 (6H, s), 2.28 (3H,
s), 2.04 ppm (3H, s); 13C NMR (CDCl3, 100 MHz): d=164.7, 160.9,
136.1, 128.6, 128.2, 127.2, 126.3, 120.6, 119.8, 66.0, 10.3, 10.3 ppm;
MS (ESI-TOF): m/z: calcd for C17H21N2O3: 301.1547; found: 301.1548
[M+H]+.
Benzyl 8-ethyl-2,3,7,9-tetramethyl-5-dipyrroketone-1-carbox-
ylate (3)
Benzyl 5-N,N-dimethylamido-3,4-dimethylpyrrole-2-carboxylate (2c)
(1.808 g, 6.02 mmol) was dissolved in warm POCl3 (9.23 g,
60.2 mmol) The mixture was stirred at 508C for 5 h and then
cooled to room temperature. Excess POCl3 was removed by evapo-
ration using a ethylene dibromide under reduced pressure to give
a red oily product that was then redissolved in CH2Cl2 (4 mL). A so-
lution of 3-ethyl-2,4-dimethylpyrrole (0.82 mL, 6.02 mmol) in CH2Cl2
(4 mL) was added into the mixture under argon. The mixture was
then stirred at 308C overnight. The reaction was monitored by UV/
Vis (reaction was stopped when extinctions at 351/399 nm reached
a maximum). A solution of sodium acetate (10 g) in water (25 mL)
was added into the mixture, which was then refluxed for 2–3 h.
After the mixture was cooled to room temperature, chloroform
(50 mLꢂ3) was used to extract the organic components, which
were washed with water, aqueous Na2CO3 solution (10%), water
again, and finally dried over anhydrous Na2SO4. The organic sol-
vents were removed under reduced pressure and then the residue
2
Fx¼Fs ꢁ ðFx=FsÞ ꢁ ðAs=AxÞ ꢁ ðnx=nsÞ
in which Fx and Fs are the fluorescence quantum yields of the
test samples and standards; Fx and Fs are the areas under the test
samples’ and standards’ emission peaks; Ax is the absorbance at
which test samples were excited; As the absorbance at which
standards were excited; nx and ns are refractive indexes of test
samples and standards.
5-Benzyloxycarbonyl-3,4-dimethylpyrrole-2-carboxylic acid
(2b)
Benzyl-3,4,5-trimethylpyrrole-2-carboxylate
17.84 mmol) was dissolved in carbon tetrachloride (270 mL). Sulfu-
ryl chloride (7.69 g, 57 mmol) was added dropwise and the result-
(2a)[21]
(4.34 g,
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1
was crystallized from Et2O. Further purification by silica gel chroma-
tography (CH2Cl2/MeOH as the eluent) gave a pale yellow product
(1.95 g), in 85.7% yield. H NMR (CDCl3, 400 MHz): d=9.20 (1H, s),
For BODIPY 1a: H NMR (CDCl3, 400 MHz): d=2.54 (3H, s), 2.40–
3
2.45 (8H, m, overlapped), 2.01(3H, s), 1.05–1.09 ppm (3H, t, J(H,H)
7.5 Hz); 13C NMR (CDCl3, 100 MHz): d=158.4, 140.4, 138.2, 137.5,
=
1
8.78 (1H, s), 7.35–7.44 (5H, m), 5.33 (2H, s), 2.38–2.42 (2H, q,
3J(H,H) =7.6 Hz), 2.36 (3H, s), 2.31 (3H, s), 2.25 (3H, s), 2.15 (3H, s),
1.04–1.08 ppm (3H, t, 3J(H,H) =7.5 Hz); 13C NMR (CDCl3, 100 MHz):
d=175.6, 161.2, 136.0, 133.0, 131.4, 128.6, 128.3, 128.2, 127.8,
127.7, 127.4, 125.4, 124.3, 120.4, 66.1, 17.3, 15.0, 11.5, 10.8, 10.3,
9.9 ppm; MS (ESI-TOF): m/z: calcd for C23H27N2O3: 379.2016: found:
379.2017 [M+H]+.
135.4, 135.2, 130.8, 127.6, 124.5, 17.1, 14.5, 14.2, 14.1, 12.9,
1
8.9 ppm; 11B NMR (CDCl3, 128 MHz): d=0.18 ppm (t, J(B,F)
=
30.2 Hz); MS (ESI-TOF): m/z: calcd for C15H17BCl2F2N2: 344.0939;
344.0937 [M+H]+.
For the 8-monochloro-BODIPY byproduct 1b: 1H NMR (CDCl3,
400 MHz): d=7.40 (1H, s), 2.53 (3H, s), 2.40–2.45 (8H, m, over-
3
lapped), 2.04 (3H, s), 1.05–1.09 ppm (3H, t, J(H,H) =7.5 Hz); 13C NMR
(CDCl3, 400 MHz): d=157.8, 140.6, 138.7, 137.5, 137.0, 134.6, 131.0,
129.2, 126.7, 17.1, 14.6, 14.1, 13.4, 12.9, 10.0 ppm; 11B NMR (CDCl3,
128 MHz): d=0.05 ppm (t, J(B,F) =30.3 Hz); MS (ESI-TOF): m/z: calcd
for C15H19BClF2N2: 310.1329; found: 310.1307 [M+H]+.
1
8-Ethyl-1-iodo-2,3,7,9-tetramethyl-5-dipyrroketone (5)
Pd/C (165 mg, 10%) was added to a 250 mL flask equipped with
a magnetic stirrer. The flask was evacuated and refilled with THF
(10 mL) and then with H2. The mixture was stirred strongly for
15 min under a H2 atmosphere. A THF (150 mL) solution of dipyrro-
ketone 3 (1.65 g, 4.36 mmol) was added to the flask under H2. The
mixture was stirred at room temperature for 12 h. The reaction
was stopped when the starting material disappeared according to
TLC analysis. The palladium catalyst was filtered through a celite
cake and washed with THF (100 mLꢂ3). The organic solutions
were combined and the solvents were removed under reduced
pressure to yield a white solid. The solid products were dissolved
in a mixture of NaHCO3 (1.87 g, 22.3 mmol)/H2O (110 mL) and
MeOH (44 mL). A solution of I2 (1.63 g, 6.42 mmol) in MeOH
(26 mL) was added dropwise into the mixture at room temperature
and brown solids precipitated out immediately. The mixture was
stirred for another 2 h at room temperature after the addition was
completed. The solids were filtered and washed with water, satu-
rated NaHCO3 (aq), water again, and hexanes to remove excess
iodine. The solids were redissolved in CH2Cl2 and dried over anhy-
drous Na2SO4. The organic solvents were removed under reduced
pressure to give a pure pale yellow product (1.36 g, 84.2%).
1H NMR: (CDCl3, 400 MHz): d=8.79 (1H, s), 8.64 (1H, s), 2.38–2.43
General procedure for the preparation of BODIPYs 6a–c
Into a 50 mL round-bottom flask was added 3,8-dichloro-1,2,5,7-
tetramethyl-BODIPY 1a (34.4 mg, 0.1 mmol) and [Pd(PPh3)4]
(10 mol%). The flask was then evacuated and refilled with argon 3
times. Dry toluene (30 mL) and organostannane regent (0.3 mmol)
were introduced into the flask. The mixture was refluxed for 6 h
under an argon atmosphere. The reaction was stopped when TLC
analysis showed the disappearance of starting material. Toluene
was removed under reduced pressure. A flash column chromatog-
raphy (CH2Cl2 as the eluent) was used to separate the crude prod-
ucts. Further purification by using a silica gel column with CH2Cl2/
hexanes or ethyl acetate/hexanes as the eluent gave the desired
disubstituted BODIPY products.
1
BODIPY 6a: Yield: 37.7 mg, 85.6%; H NMR (CDCl3, 400 MHz): d=
7.50–7.55 (3H, m), 7.02–7.19 (3H, m), 2.51 (3H, s), 2.31–2.36 (2H, q,
3J(H,H) =7.6 Hz), 1.97 (3H, s), 1.53 (6H, s), 0.99–1.03 ppm (3H, t,
3J(H,H) =7.6 Hz); 13C NMR (CDCl3, 100 MHz): d=158.6, 145.4, 140.4,
138.2, 135.6, 134.9, 133.5, 133.0, 132.8, 132.1, 130.6, 130.5, 128.1,
127.7, 127.7, 127.5, 127.0, 17.1, 14.4, 13.0, 11.3, 11.1, 10.4 ppm;
3
1
(2H, q, J(H,H) =6.9 Hz), 2.45 (3H, s), 2.17 (3H, s), 2.13 (3H, s), 2.00
11B NMR (CDCl3, 128 MHz): d=0.66 ppm (t, J(B,F) =32.3 Hz); MS (ESI-
(3H, s), 1.06–1.10 ppm (3H, t, 3J(H,H) =6.8 Hz); 13C NMR (CDCl3,
100 MHz): d=174.5, 133.6, 131.1, 126.9, 126.5, 126.4, 124.9, 124.8,
73.2, 17.3, 15.1, 11.9, 11.5, 11.2, 10.8 ppm; MS (ESI-TOF): m/z: calcd
for C15H20IN2O: 371.0615; found: 371.0613 [M+H]+.
TOF): m/z: calcd for C23H23BF2N2S2: 440.1473; found: 440.1445
[M+H]+.
1
BODIPY 6b: Yield: 25.8 mg, 63.2%; H NMR (CDCl3, 400 MHz): d=
7.49–7.64 (3H, m), 6.44–6.59 (3H, m), 2.57 (3H, s), 2.32–2.38 (2H, q,
3J(H,H) =7.4 Hz), 2.17 (3H, s), 1.52 (3H, s), 1.50 (3H, s), 1.01–1.05 ppm
(3H, t, 3J(H,H) =7.4 Hz); 13C NMR (CDCl3, 100 MHz): d=157.9, 147.3,
146.0, 143.6, 142.5, 142.4, 139.2, 138.7, 134.4, 133.8, 133.5, 127.7,
126.3, 115.2(t), 112.3, 111.7, 111.5, 17.1, 14.4, 13.0, 10.9, 10.4 ppm;
3,8-Dichloro-6-ethyl-1,2,5,7-tetramethyl-BODIPY (1a)
Iododipyrroketone 5 (1.36 g, 3.67 mmol) was dissolved in chloro-
form (300 mL). The flask was evacuated and refilled with argon.
Phosgene solution (15% in toluene, 26 mL) was added into the
mixture and then it was stirred overnight at room temperature.
The reaction was stopped when the starting materials were totally
consumed. N2 was purged into the flask to remove extra phosgene
into a beaker containing saturated NaHCO3 solution. The organic
solvents were removed under reduced pressure to obtain a red
solid. The red solid was added into another 500 mL round-bottom
flask equipped with a stirrer. The flask was evacuated and refilled
with argon. Chloroform (300 mL) and N,N-diisopropylethylamine
(3.32 g, 25.7 mmol) were added under argon. The mixture was
then stirred for 30 min. BF3·OEt2 (5.2 g, 36.7 mmol) was added into
the mixture which was stirred for another 10 h. The organic solu-
tion was washed with water, saturated NaHCO3 solution, and brine.
After drying over anhydrous Na2SO4, the organic solvents were re-
moved under reduced pressure. Further purification by silica gel
column chromatography with CH2Cl2/hexanes as the eluent gave
the titled BODIPY 1a (0.99 g, 78.2%) and its 8-monochloro-BODIPY
byproduct (68 mg, 6%).
1
11B NMR (CDCl3, 128 MHz): d=0.87 ppm (t, J(B,F) =32.7 Hz); MS (ESI-
TOF): m/z: calcd for C23H23BF2N2O2: 408.193; found: 408.1905
[M+H]+.
1
BODIPY 6c: Yield: 34.6 mg, 80.8%; H NMR (CDCl3, 400 MHz): d=
7.35–7.49 (10H, m), 2.46 (3H, s), 2.27–2.33 (2H, q, 3J(H,H) =7.4 Hz),
3
1.79 (3H, s), 1.32 (3H, s), 1.35 (3H, s), 0.96–0.99 ppm (3H, t, J(H,H)
=
7.4 Hz); 13C NMR (CDCl3, 100 MHz): d=156.8, 153.2, 141.3, 139.8,
138.2, 135.8, 134.0, 132.9, 131.8, 130.9, 130.0, 129.1, 128.9, 128.4,
128.3, 127.6, 126.4, 17.1, 14.4, 12.8, 12.1, 11.8, 9.7 ppm; 11B NMR
1
(CDCl3, 128 MHz): d=0.67 ppm (t, J(B,F) =32.4 Hz); MS (ESI-TOF): m/
z: calcd for C27H26BFN2: 408.2282; found: 408.2284 [MꢀF]+.
General procedure for the preparation of BODIPYs 7a–c
Into a 100 mL round-bottom flask was added BODIPY 1a (34.4 mg,
0.1 mmol) and [Pd(PPh3)4] (10 mol%). The flask was then evacuated
and refilled with argon 3 times. Dry toluene (60 mL) and organo-
stannane regent (0.1 mmol) were introduced into the flask. The
mixture was refluxed at 808C under Ar. The reaction was stopped
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when TLC analysis showed the disappearance of starting material.
Toluene was removed under reduced pressure. Silica gel flash
column chromatography was used for purification of the products,
eluting with dichloromethane/hexanes or ethyl acetate/hexanes.
(1H, m), 6.59 (1H, m), 6.48–6.49 (1H, m), 2.51 (3H, s), 2.32–2.37
3
(2H, q, J(H,H) =7.6 Hz), 1.99 (3H, s), 1.53 (6H, s), 1.00–1.04 ppm (3H,
3
t, J(H,H) =7.5 Hz); 13C NMR (CDCl3, 100 MHz): d=159.4, 146.0, 145.8,
142.6, 140.0, 137.9, 134.8, 134.1, 132.8, 132.6, 130.6 (t), 127.8, 127.6,
127.1, 127.0, 111.7, 112.5, 17.1, 14.4, 13.1, 10.7, 10.5, 10.4 ppm;
BODIPY 7a: Yield: 33 mg, 84%; 1H NMR (CDCl3, 400 MHz): d=
1
11B NMR (CDCl3, 128 MHz): d=0.68 ppm (t, J(B,F) =32.2 Hz); MS (ESI-
7.52–7.54 (1H, q, 3J(H,H) =4.0, 4J(H,H) =1.1 Hz), 7.14–7.16 (1H, q,
4
3J(H,H) =3.5, 3J(H,H) =1.5 Hz); 6.99–7.00 (1H, q, 3J(H,H) =2.3, J(H,H)
=
TOF): m/z: calcd for C23H24BF2N2OS: 424.1701; found: 424.1674
[M+H]+.
3
1.1 Hz), 2.58 (3H, s), 2.31–2.37 (2H, q, J(H,H) =7.5 Hz), 1.92 (3H, s),
1.52 (3H, s), 1.48 (3H, s), 1.00–1.03 ppm (3H, t, 3J(H,H) =7.6 Hz);
13C NMR (CDCl3, 100 MHz): d=159.4, 141.1, 139.0, 138.1, 135.1,
134.8, 133.4, 132.7, 130.2, 128.1, 127.7, 127.6, 124.3, 17.1, 14.3, 13.0,
11.3, 11.1, 8.8 ppm; 11B NMR (CDCl3, 128 MHz): d=0.35 ppm (t,
1J(B,F) =31.0 Hz); MS (ESI-TOF): m/z: calcd for C19H20BClF2N2S:
392.1206; found: 392.1208 [M+H]+.
BODIPY 10: Into a 50 mL round-bottom flask was added meso-sub-
stituted BODIPY 7b (18.8 mg, 0.05 mmol) and [Pd(PPh3)4]
(10 mol%). The flask was then evacuated and refilled with argon 3
times. Dry toluene (4 mL) and trimethyl[(tributylstannyl)ethynyl]si-
lane (0.06 mmol) were introduced into the flask. The mixture was
refluxed for 6 h under an argon atmosphere. The reaction was
stopped when TLC analysis showed the disappearance of starting
material. Toluene was removed under reduced pressure. A flash
column chromatography (CH2Cl2 as eluent) was used to separate
the crude products. Further purification by silica gel column chro-
matography with ethyl acetate/hexanes as the eluent gave the de-
sired disubstituted BODIPY product. Yield: 12.7 mg, 58%; 1H NMR
BODIPY 7b: Yield: 29 mg, 77%; 1H NMR (CDCl3, 400 MHz): 7.63–
3
3
7.64 (1H, m), 6.56–6.57 (1H, q, J(H,H) =1.8, J(H,H) =1.5 Hz), 6.45–6.46
3
(1H, m), 2.57 (3H, s), 2.32–2.38 (2H, q, J(H,H) =7.6 Hz), 1.93 (3H, s),
1.52 (3H, s), 1.49 (3H, s), 1.01–1.05 ppm (3H, t, 3J(H,H) =7.5 Hz);
13C NMR (CDCl3, 100 MHz): d=160.3, 145.1, 142.8, 140.8, 139.3,
137.7, 135.1, 134.1, 130.6, 126.9, 124.3, 111.8, 111.6, 17.1, 14.3, 13.1,
10.8, 10.6, 8.8 ppm; 11B NMR (CDCl3, 128 MHz): d=0.32 ppm (t,
1J(B,F) =30.9 Hz); MS (ESI-TOF): m/z: calcd for C19H20BClF2N2O:
376.1434; found: 376.1410 [M+H]+.
3
(CDCl3, 400 MHz): d=7.62 (1H, m), 6.54–6.56 (1H, q, J(H,H) =1.7 Hz,
3J(H,H) =1.5 Hz), 6.43–6.44 (1H, m), 2.59 (3H, s), 2.32–2.37 (2H, q,
3J(H,H) =7.5 Hz), 1.99 (3H, s), 1.52 (3H, s), 1.45 (3H, s), 1.00–1.04 (3H,
3
t, J(H,H) =7.5 Hz), 0.31 ppm (9H, s); 13C NMR (CDCl3, 100 MHz): d=
1
BODIPY 7c: Yield: 32.4 mg, 83.8%; H NMR (CDCl3, 400 MHz): d=
162.1, 145.8, 143.0, 141.1, 136.3, 135.8, 132.7, 132.6, 132.2, 126.9,
112.0, 111.8, 109.3, 97.3, 17.5, 14.6, 13.7, 10.9, 10.7, 10.0, 0.2 ppm;
3
7.28–7.50 (5H, m), 2.58(3H, s), 2.29–2.35 (2H, q, J(H,H) =7.5 Hz), 1.90
3
(3H, s), 1.28 (3H, s), 1.30 (3H, s), 0.98–1.02 ppm (3H, t, J(H,H)
=
1
11B NMR (CDCl3, 128 MHz): d=0.28 ppm (t, J(B,F) =30.0 Hz); MS (ESI-
7.5 Hz); 13C NMR (CDCl3, 100 MHz): d=158.5, 140.8, 140.5, 138.4,
137.9, 135.1, 134.7, 132.2, 129.4, 129.2, 129.1, 128.1, 124.0, 17.1,
14.4, 12.9, 12.1, 11.9, 8.8 ppm; 11B NMR (CDCl3, 128 MHz): d=
0.41 ppm (t, 1J(B,F) =31.1 Hz); MS (ESI-TOF): m/z: calcd for
C21H22BClFN2: 366.1579; 366.1567 [MꢀF]+.
TOF): m/z: calcd for C24H30BF2N2OSi: 438.2219; found: 438.2223
[M+H]+.
General procedure for the preparation of BODIPYs 11–13
BODIPY 8: Into a 50 mL round-bottom flask was added BODIPY 7a
(19.6 mg, 0.05 mmol) and [Pd(PPh3)4] (10 mol%). The flask was then
evacuated and refilled with argon 3 times. Dry toluene (20 mL) and
tributyl-(2-furyl)stannane (0.1 mmol) were introduced into the flask.
The mixture was refluxed for 6 h under Ar. The reaction was
stopped when TLC analysis showed the disappearance of starting
materials. Toluene was removed under reduced pressure. A flash
column chromatography (CH2Cl2 as the eluent) was used to sepa-
rate the crude products. Further purification by silica gel column
chromatography with ethyl acetate/hexanes as the eluent gave the
desired disubstituted BODIPY product. Yield: 19.3 mg, 91%;
1H NMR (CDCl3, 400 MHz): d=7.61 (1H, m), 7.52–7.53 (1H, m),
7.46–7.47 (1H, m), 7.15–7.17 (1H, m), 7.00–7.01 (1H, m), 6.59–6.60
Into a 5 mL round-bottom flask was added BODIPY 1a (17.2 mg,
0.05 mmol), nucleophile (1–10 equiv), and K2CO3 (13.8 mg,
0.1 mmol). CH2Cl2 (0.5 mL) was added into the flask. The mixture
was stirred at room temperature. The reaction was stopped when
TLC analysis showed the disappearance of starting material. The
crude product was subjected to a short flash column chromatogra-
phy (CH2Cl2 as eluents) to remove polar byproducts. Further purifi-
cation by silica gel column chromatography with CH2Cl2/hexanes
or ethyl acetate/hexanes as the eluent gave the desired BODIPY
products.
BODIPY 11: Yield: 19.1 mg, 94.9%; 1H NMR (CDCl3, 400 MHz): d=
6.99–7.34 (5H, m), 2.57 (3H, s), 2.34–2.38 (2H, q, 3J(H,H) =7.1 Hz),
3
3
2.01 (3H, s), 1.98 (3H, s), 1.93 (3H, s), 1.01–1.04 ppm (3H, t, J(H,H)
=
(1H, m), 2.57 (3H, s), 2.30–2.37 (2H, q, J(H,H) =7.4 Hz), 2.15 (3H, s),
7.3 Hz); 13C NMR (CDCl3, 100 MHz): d=158.6, 157.5, 150.5, 138.2,
137.8, 135.2, 133.9, 130.5, 128.3, 125.6, 123.5, 123.0, 114.7, 16.9,
14.4, 13.0, 12.0, 11.7, 8.6 ppm; 11B NMR (CDCl3, 128 MHz): d=
0.36 ppm (t, 1J(B,F) =30.5 Hz); MS (ESI-TOF): m/z: calcd for
C21H23BClF2N2O: 402.1591; found: 402.1564 [M+H]+.
3
1.52 (6H, s), 1.00–1.04 ppm (3H, t, J(H,H) =7.5 Hz); 13C NMR (CDCl3,
100 MHz): d=157.2, 147.2, 143.5, 141.8, 139.7, 139.0, 135.8, 134.5,
133.1, 132.8, 128.2, 127.8, 127.6, 127.4, 114.9 (t), 112.2, 17.1, 14.4,
12.9, 11.1, 11.0, 10.9 ppm; 11B NMR (CDCl3, 128 MHz): d=0.84 ppm
(t, 1J(B,F) =32.8 Hz); MS (ESI-TOF): m/z calcd for C23H23BF2N2NaOS:
446.1521; 446.1517 [M+Na]+.
1
BODIPY 12: Yield: 17.4 mg, 86.6%; H NMR (400 MHz, CDCl3): d=
6.93–7.25 (5H, m), 6.55 (1H, s), 2.55 (3H, s), 2.31–2.37 (2H, q,
BODIPY 9: Into a 50 mL round bottom flask was added BODIPY 7b
(18.8 mg, 0.05 mmol) and [Pd(PPh3)4] (10 mol%). The flask was then
evacuated and refilled with argon for 3 times. Dry toluene (20 mL)
and 2-(tributylstannyl)thiophene (0.15 mmol) were introduced into
the flask. The mixture was refluxed for 6 h under Ar. The reaction
was stopped when TLC analysis showed the disappearance of
starting material. Toluene was removed under reduced pressure. A
flash column chromatography (CH2Cl2 as eluent) was used to give
the crude products. Further purification by silica gel column chro-
matography with ethyl acetate/hexanes as the eluent gave the de-
sired disubstituted BODIPY product. Yield: 19 mg, 89.6%; 1H NMR
(CDCl3, 400 MHz): d=7.67 (1H, m), 7.51–7.56 (2H, m), 7.18–7.20
3J(H,H) =7.4 Hz), 1.98 (3H, s), 1.91 (3H, s), 1.89 (3H, s), 1.00–1.03 ppm
3
(3H, t, J(H,H) =7.6 Hz); 13C (100 MHz, CDCl3): d=153.5, 143.5, 140.6,
135.3, 134.9, 133.0, 132.6, 129.8, 127.2, 125.5, 122.8, 118.0, 17.0,
14.7, 12.9, 12.8, 12.64, 8.8 ppm; 11B NMR (CDCl3, 128 MHz): d=
0.47 ppm (t, 1J(B,F) =31.1 Hz); MS (ESI-TOF): m/z: calcd for
C21H24BClF2N3: 401.1751; found: 401.1725 [M+H]+.
BODIPY 13: Yield: 24.2 mg, 93%; 1H NMR (400 MHz, CDCl3): d=
7.05–7.22 (8H, m), 2.60 (3H, s), 2.36–2.41 (5H, m, overlapped), 2.31
3
(6H, s), 2.29 (3H, s), 1.72 (3H, s), 1.01–1.04 ppm (3H, t, J(H,H)
=
6.0 Hz); 13C NMR (100 MHz, CDCl3): d=160.4, 143.6, 141.9, 138.2,
137.2, 136.3, 135.9, 134.3, 133.0, 132.8, 132.1, 131.7, 130.3, 129.8,
&
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Chem. Eur. J. 2015, 21, 1 – 13
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ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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129.4, 126.3, 21.1, 21.0, 17.2, 14.5, 14.4, 13.2, 10.1 ppm; 11B NMR
(CDCl3, 128 MHz): d=0.51 ppm (t, J(B,F) =31.5 Hz); MS (ESI-TOF): m/
z: calcd for C29H32BF2N2S2: 520.2099; found: 520.2085 [M+H]+.
117.9, 114.1, 55.4, 18.4, 14.0, 12.2, 11.6, 9.8 ppm; 11B NMR (CDCl3,
128 MHz): d=0.90 ppm (t, J(B,F) =32.7 Hz); MS (ESI-TOF): m/z: calcd
for C35H33BF2N2O: 545.2685; found: 545.2687 [M+H]+.
1
1
BODIPY 17: Into a 50 mL round-bottom flask was added BODIPY
6c (21.4 mg, 0.05 mmol). The flask was then evacuated and refilled
with argon 3 times. Dry toluene (10 mL) was added. The tempera-
ture was raised to 1108C. A solution of DDQ (56.8 mg, 0.25 mmol)
in toluene (10 mL) was added slowly into the mixture, which was
stirred and refluxed under an argon atmosphere. The reaction was
stopped when TLC analysis showed the disappearance of starting
material. Solvents were removed under reduced pressure to give
the crude product. Further purification by silica gel column chro-
matography or preparative TLC plates with ethyl acetate/hexanes
as the eluent gave BODIPY 17 (5.7 mg, 25.8% yield). 1H NMR
(400 Hz, CDCl3): d=10.30 (1H, s), 7.37–7.59 (5H, m), 2.67–2.71 (2H,
q, 3J(H,H) =7.4 Hz), 1.84 (3H, s), 1.44 (3H, s), 1.31 (3H, s), 1.00–
BODIPY 14: Into a 5 mL round-bottom flask were added BODIPY
7c (19.3 mg, 0.05 mmol), thiolcarborane (88 mg, 0.5 mmol), and
K2CO3 (13.8 mg, 0.1 mmol). CH2Cl2 (1 mL) was added into the flask.
The mixture was then stirred at room temperature. The reaction
was quenched with water when TLC analysis showed the disap-
pearance of starting material. CH2Cl2 (10 mLꢂ3) was used to ex-
tract the organic components. Organic solvents were combined,
dried over anhydrous Na2SO4, and evaporated under reduced pres-
sure to give the crude product. Further purification by silica gel
column chromatography with ethyl acetate/hexanes as the eluent
gave the titled product (17.7 mg, 67.3%). 1H NMR (400 MHz,
CDCl3): d=7.24–7.5 (5H, m), 4.59 (1H, s), 1.76–3.34 (10H, m), 2.63
3
(3H, s), 2.32–2.38 (2H, q, J(H,H) =7.6 Hz), 2.04 (3H, s), 1.36 (3H, s),
3
1.03 ppm (3H, t, J(H,H) =7.1 Hz); 13C NMR (400 Hz, CDCl3): d=186.3,
1.29 (3H, s), 0.99–1.03 ppm (3H, t, 3J(H,H) =7.5 Hz); 13C NMR
(100 MHz, CDCl3): d=165.0, 143.4, 141.6, 137.3, 135.5, 134.9, 134.7,
134.2, 133.3, 132.5, 129.4(t), 128.0, 127.9, 66.3, 66.2, 17.1, 14.1, 13.6,
12.2, 12.1, 11.1 ppm; 11B NMR (CDCl3, 128 MHz): d=0.29 (1B, t,
164.5, 144.7, 144.5, 141.2, 137.2, 136.3, 135.8, 134.9, 132.6, 131.5,
130.9, 130.0, 129.6, 129.5, 129.3, 128.1, 127.8, 17.6, 14.3, 12.9, 10.7,
1
10.0 ppm; 11B NMR (CDCl3, 128 MHz): d=0.69 ppm (t, J(B,F)
=
1
1
1J(B,F) =31.1 Hz), ꢀ0.85 (1B, d, J(B,H) =142 Hz), ꢀ4.74 (1B, d, J(B,H)
=
32.1 Hz); MS (ESI-TOF): m/z: calcd for C27H26BF2N2O: 442.2137;
found: 442.2145 [M+H]+.
128 Hz), ꢀ10.1 to ꢀ12.92 ppm (8B, m); MS (ESI-TOF): m/z: calcd for
C23H24B11F2N2S: 527.3520; found: 527.3512 [M+H]+.
Crystal data
BODIPY 15: Into a 50 mL round-bottom flask was added meso-sub-
stiutued BODIPY 11 (10 mg, 0.025 mmol) and [Pd(PPh3)4]
(10 mol%). The flask was then evacuated and refilled with argon 3
times. Dry toluene (20 mL) and 2-(tributylstannyl)thiophene
(0.05 mmol) were introduced into the flask. The mixture was re-
fluxed for 6 h under an argon atmosphere. The reaction was
stopped when TLC analysis showed the disappearance of starting
material. Toluene was removed under reduced pressure. A flash
column chromatography (CH2Cl2 as the eluent) was used to obtain
the crude product. Further purification by silica gel column chro-
matography with ethyl acetate/hexanes as the eluent gave the de-
Diffraction data were collected at low temperature (90–105 K) on
either a Nonius KappaCCD diffractometer equipped with MoKa radi-
ation (l=0.71073 ꢁ) or a Bruker Kappa Apex-II DUO diffractometer
equipped with Mo or CuKa radiation (l=1.54184 ꢁ). Refinement
was by full-matrix least squares using SHELXL, with H atoms in ide-
alized positions, except for those on N in 3, 4, and 12, which were
refined. BODIPYS 1a and 16 have two independent molecules, and
1b has four. 1a, 6b, and 16 were nonmerohedral twins, and disor-
der was present in 1a, 6a–c, 8, 11, and 12. Compounds 1a and 17
were chloroform solvates. The absolute structures of both noncen-
trosymmetric crystals 1b and 7c were determined. For 1a:
C15H17BCl2F2N2·0.5CHCl3, triclinic P-1, a=8.4888(3), b=13.9111(6),
c=14.8676(6) ꢁ, a=86.609(3), b=88.646(2), g=89.580(2)8, Z=4,
T=90 K, R=0.067; 1b: C15H18BClF2N2, monoclinic P21, a=
15.4384(5), b=11.5896(4), c=16.8479(5) ꢁ, b=99.215(2)8, Z=8, T=
90 K, R=0.047; 3: C23H26N2O3, monoclinic P21/n, a=7.7071(6), b=
12.3770(9), c=21.4131(17) ꢁ, b=92.673(4)8, Z=4, T=100 K, R=
0.045; 4: [C23H26ClN2O2]Cl, triclinic P-1, a=8.1637(4), b=9.5889(5),
c=13.6082(8) ꢁ, a=94.850(3), b=97.737(2), g=92.855(2)8, Z=2,
T=100 K, R=0.033; 6a: C23H23BF2N2S2, triclinic P-1, a=9.5771(14),
b=10.3269(15), c=11.567(2) ꢁ, a=77.851(8), b=66.885(6), g=
79.384(7)8, Z=2, T=100 K, R=0.041; 6b: C23H23BF2N2O2, triclinic P-
1, a=9.362(2), b=10.155(2), c=11.682(3) ꢁ, a=76.840(6), b=
66.796(6), g=77.094(6)8, Z=2, T=90 K, R=0.089; 6c: C27H27BF2N2,
monoclinic P21/n, a=11.4039(6), b=7.9247(4), c=24.2010(12) ꢁ,
b=91.650(3)8, Z=4, T=90 K, R=0.047; 7c: C21H22BClF2N2, mono-
clinic Pc, a=7.6918(2), b=8.2818(2), c=14.8858(4) ꢁ, b=
94.762(2)8, Z=2, T=105 K, R=0.035; 8: C23H23BF2N2OS, triclinic P-1,
a=9.5378(3), b=10.1969(3), c=11.5554(4) ꢁ, a=76.414(2), b=
1
sired product. Yield: 10.2 mg, 90.6%; H NMR (400 MHz, CDCl3): d=
3
7.50–7.53 (2H, m), 7.32–7.36 (2H, m), 7.17–7.19 (1H, q, J(H,H) =3.6,
3J(H,H) =1.5 Hz), 7.05–7.10 (3H, m), 2.50 (3H, s), 2.31–2.37 (2H, q,
3J(H,H) =7.6 Hz), 2.04 (3H, s), 2.02 (3H, s), 1.99 (3H, s), 0.99–1.03 ppm
3
(3H, t, J(H,H) =7.6 Hz); 13C (100 MHz, CDCl3): d=157.8, 157.7, 150.9,
145.4, 137.4, 135.3, 133.6, 132.7, 130.4 (t), 130.1, 128.3, 127.6, 127.0,
126.7, 123.0, 122.8, 114.9, 17.0, 14.5, 13.0, 11.9, 11.7, 10.2 ppm;
1
11B NMR (CDCl3, 128 MHz): d=0.64 ppm (t, J(B,F) =32.0 Hz); MS (ESI-
TOF): m/z: calcd for C25H26BF2N2OS: 450.1858; found: 450.1831
[M+H]+.
BODIPY 16: Into a 50 mL round-bottom flask was added BODIPY
6c (21.4 mg, 0.05 mmol), molecular sieves, and methyl 4-formylani-
sole (68 mg, 0.5 mmol) in toluene (10 mL). p-TsOH (10 mg) and pi-
peridine (0.1 mL) were added into the mixture. The mixture was
stirred and refluxed for 72 h under an argon atmosphere. The reac-
tion was stopped when TLC analysis showed the disappearance of
starting material. The mixture was cooled to room temperature
and filtered to remove the moleculer sieves. The filtrate was
poured into water (20 mL) and CH2Cl2 (20 mLꢂ3) was used to ex-
tract the organic components. The organic solvents were com-
bined, dried over anhydrous Na2SO4, and evaporated under re-
duced pressure to give the crude product. Further purification by
silica gel column chromatography with ethyl acetate/hexanes as
66.800(2),
g=78.800(2)8,
Z=2,
T=90 K,
R=0.040;
9:
C23H23BF2N2OS, triclinic P-1, a=9.4222(2), b=10.2488(2), c=
11.6233(3) ꢁ, a=78.492(2), b=66.845(2), g=77.813(2)8, Z=2, T=
90 K, R=0.043; 10: C24H29BF2N2OSi, monoclinic P21/c, a=6.9871(2),
b=22.5959(8), c=14.6041(6) ꢁ, b=93.098(2)8, Z=4, T=90 K, R=
0.041; 11: C21H22BClF2N2O, triclinic P-1, a=9.4115(3), b=10.4033(4),
c=11.3995(4) ꢁ, a=66.223(2), b=77.459(2), g=68.527(2)8, Z=2,
T=90 K, R=0.051; 12: C21H23BClF2N3, monoclinic C2/c, a=
21.8367(10), b=8.9694(4), c=21.9939(8) ꢁ, b=114.299(2)8, Z=8,
T=90 K, R=0.050; 14: C23H33B11F2N2S, triclinic P-1, a=6.9030(7),
the eluent gave the styryl-BODIPY 16 (14.2 mg, 52%). 1H NMR
3
(400 Hz, CDCl3): d=7.13–7.60 (14H, m), 6.85–6.87 (2H, d, J(H,H)
=
8 Hz), 3.83 (3H, s), 2.56–2.62 (2H, q, 3J(H,H) =7.5 Hz), 1.80 (3H, s),
1.36 (6H, s), 1.13–1.16 ppm (3H, t, J(H,H) =7.3 Hz); 13C NMR (400 Hz,
3
CDCl3): d=160.3, 154.1, 152.1, 140.3, 140.1, 138.4, 136.2, 136.1,
133.9, 132.9, 132.8, 131.9, 130.0, 129.1, 128.9, 128.5, 127.7, 127.2,
Chem. Eur. J. 2015, 21, 1 – 13
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Acknowledgements
This work was supported by the National Science Foundation,
grant CHE-1362641, and the National Institutes of Heath, grant
CA132861.
Keywords: addition/elimination · BODIPY · fluorescence · Pd0-
catalyzed coupling · oxidation · substitution
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Received: December 18, 2014
Published online on && &&, 0000
&
&
Chem. Eur. J. 2015, 21, 1 – 13
www.chemeurj.org
12
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!

Full Paper
FULL PAPER
Reactivity of 3,8-dichloro-6-ethyl-
1,2,5,7-tetramethyl-BODIPY
&
Asymmetric Synthesis
N. Zhao, M. G. H. Vicente,* F. R. Fronczek,
K. M. Smith
(BODIPY=4,4-difluoro-4-bora-3a,4a-
diaza-s-indacene), synthesized from an
unsymmetric dipyrroketone, under four
types of reactions is reported. The struc-
tural and spectroscopic properties of
the new BODIPYs are discussed, includ-
ing sixteen X-ray structures.
&& – &&
Synthesis of 3,8-Dichloro-6-ethyl-
1,2,5,7-tetramethyl–BODIPY from an
Asymmetric Dipyrroketone and
Reactivity Studies at the 3,5,8-
Positions
Chem. Eur. J. 2015, 21, 1 – 13
www.chemeurj.org
13
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ