Scope and limitations of the liebeskind-srogl cross-coupling reactions involving the biellmann BODIPY

Article abstract of DOI:10.1021/acs.joc.5b00731

Several new examples of meso-(het)arylBODIPY were prepared via the Liebeskind-Srogl (L-S) cross-coupling reaction of the Biellmann BODIPYs (1a,b) and aryl- and heteroarylboronic acids in good to excellent yield. It was shown that this reaction could be ca

Full text of DOI:10.1021/acs.joc.5b00731

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Article
Scope and Limitations of the Liebeskind-Srogl Cross-
Coupling Reactions Involving the Biellmann BODIPY
Lourdes Betancourt-Mendiola, Ismael Valois-Escamilla, Teresa Arbeloa, Jorge Bañuelos,
Iñigo Lopez Arbeloa, Juan Orlando Flores-Rizo, Rongrong Hu, Erik Lager, Cesar Fernando
Azael Gómez-Durán, José Luis Belmonte-Vázquez, Mayra Rosario Martínez-Gonzalez, Ismael
Javier Arroyo, Carlos Alberto Osorio-Martinez, Enrique Alvarado-Martínez, Arlette Urías-
Benavides, Brenda Daniela Gutierrez-Ramos, Ben Zhong Tang, and Eduardo Peña-Cabrera
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 12 May 2015
Downloaded from http://pubs.acs.org on May 12, 2015
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Scope and Limitations of the LiebeskindꢀSrogl CrossꢀCoupling
Reactions Involving the Biellmann BODIPY.
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Lourdes BetancourtꢀMendiola,† Ismael ValoisꢀEscamilla,† Teresa Arbeloa, ¥ Jorge
Bañuelos,*, ¥ Iñigo López Arbeloa,¥ Juan O. FloresꢀRizo,† Rongrong Hu,‡ Erik Lager,†
César F. A. GómezꢀDurán,† José L. BelmonteꢀVázquez,† Mayra R. MartínezꢀGonzález,†
Ismael J. Arroyo,† Carlos A. OsorioꢀMartínez,† Enrique AlvaradoꢀMartínez,† Arlette
UríasꢀBenavides,† Brenda D. GutiérrezꢀRamos,† Ben Zhong Tang,‡ and Eduardo Peñaꢀ
Cabrera*,†
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† Departamento de Química, Universidad de Guanajuato, Col. Noria Alta S/N,
Guanajuato, Gto. 36050 Mexico.
¥ Departamento de Química Física, Universidad del País VascoꢀEHU, Apartado 644,
48080, Bilbao, Spain.
‡ Department of Chemistry, The Hong Kong University of Science & Technology, Clear
Water Bay, Kowloon, Hong Kong, China.
Eꢀmail: eduardop@ugto.mx, jorge.banuelos@ehu.es
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Abstract
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Several new examples of mesoꢀ(het)arylBODIPY were prepared via the LiebeskindꢀSrogl
(LꢀS) crossꢀcoupling reaction of the Biellmann BODIPYs (1a,b) and arylꢀ and
heteroarylboronic acids in good to excellent yield. It was shown that this reaction could
be carried out under microwave heating shortening reaction times and/ or increasing the
yield. It was illustrated that organostannanes also participate in the LꢀS reaction to give
the corresponding BODIPY analogues in short reaction times and also with good to
excellent yields. We analyze the role of the substituent at the sensitive meso position in
the photophysical signatures of these compounds. In particular, the rotational motion of
the aryl ring and the electron donor ability of the anchored moieties rule the nonꢀradiative
pathways, and hence have a deep impact in the fluorescence efficiency.
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Introduction
Truly remarkable applications of dipyrrometheneꢀBF2 fluorophores 1 (BODIPYs®)1
continue to appear in the literature. These fluorescent compounds were first reported by
Treibs and Kreuzer in 1968.2 Little did they know about the great impact these analogues
were to have in so many disciplines. The properties of this family of compounds are
reported in excellent reviews.3
Some relevant examples of their applications include the tagging of biomolecules,4 as
components of supramolecular lightꢀharvesting systems,5 in the construction of dye
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sensitized solar cells,6 as sensors,7 as components of fluorescent nanocars,8 as
nanoparticle conjugates,9 as ligands for human βꢀadrenoceptors,10 as components of bulk
heterojunction solar cells,11 in realꢀtime PCR methods,12 and to visualize Langerhans
islets,13 and as a quality control in milk,14 among others.
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Assorted methods exist in the literature dealing with the functionalization of the BODIPY
1ꢀ7 positions.15 The importance of mesoꢀsubstituted bodipy analogues was pointed out by
Nagano et al.16 They considered the bodipy general structure as a twoꢀcomponent entity
(Figure 1), the bodipy portion (in red) as the fluorophore and the aryl moiety (in blue) as
the fluorescent switch, that regulates the quantum yields, at least in the 1,7ꢀ
dimethylbodipy derivatives.
FIGURE 1. Roles of the fragments of a mesoꢀarylsubstituted BODIPY.
Additionally, the meso position is the most sensitive to substituents effects because, upon
excitation, an important variation in the electron density takes place at that site.17 From
the strategic point of view, the meso position is arguably the most important because in
the majority of the applications that have been devised for BODIPYs, it is the position of
choice for the attachment of the substrate to study.18
In the initial contribution of this laboratory,19 we reported a mild method that allowed the
introduction of a series of functional groups at the mesoꢀposition via the LiebeskindꢀSrogl
(LꢀS) crossꢀcoupling20 under neutral conditions (Scheme 1). The key component of such
process was 8ꢀmethylthioBODIPY 1a, henceforth termed the Biellmann BODIPY.21 The
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structures of the BODIPY analogues prepared by this methodology (2ꢀ20) are shown in
Chart 1.
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SCHEME 1. Application of the LiebeskindꢀSrogl crossꢀcoupling in the synthesis of
mesoꢀsubstituted BODIPY analogues using the Biellmann BODIPY 1.
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In that contribution, the advantages of this methodology over the typical acidꢀcatalyzed
condensation of an aldehyde and an excess amount of pyrrole (the Lindsey22 conditions)
method were pointed out. Summarizing, the main shortcomings of the Lindsey
methodology include: a separate synthesis of the starting aldehyde if it is not
commercially available, cumbersome purifications, incompatibility of the substituents on
the het(aryl) ring of the aldehyde to acidic conditions, oxidation, and strong Lewisꢀacid
exposure (BF3).
Chart 1
OMe
OMe
N
N
F
B
F
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Br
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F
10 pꢀBr
11 mꢀBr
12 oꢀBr
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O
N
N
F
B
F
15 X = S
16 X = O
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24
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In two further contributions that demonstrated the usefulness of boronic acids as partners
in the LꢀS crossꢀcoupling, derivatives of the type 21ꢀ24 were prepared.23
We have also demonstrated that the Biellmann BODIPY 1 engages in a desulfitative
reduction to give the parent unsubstituted BODIPY dye,24 in SNArꢀlike processes to
displace the 8ꢀmethylthio group by amines,25 phenols and alcohols,26 and Cꢀcentered soft
nucleophiles.27 In a recent contribution, we have shown that carbohydrateꢀBODIPY
hybrids could be prepared in a oneꢀpot sequence that entailed a LꢀS crossꢀcoupling
followed by a copperꢀcatalyzed azideꢀalkyne reaction.28
We wish to disclose herein a more inꢀdepth study of the scope and limitations of the
Biellmann BODIPY as participant in crossꢀcoupling reactions leading to the synthesis of
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mesoꢀsubstituted BODIPY dyes, as well as the optical data of selected examples prepared
by this methodology. We seek to demonstrate that both the Biellmann BODIPYs 1a and
its alkylated analogue 1b are privileged starting materials for the efficient and
straightforward preparation of assorted BODIPY derivatives. The advantages of this
process are more relevant since both 1a, and 1b are now commercially available.
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Results and Discussion
CrossꢀCouplings with Boronic Acids. Following the reaction conditions showed in
Scheme 1, derivatives 25ꢀ47 were prepared (Chart 2).
Chart 2. Synthesis of mesoꢀsubstituted BODIPY dyes.a
29, 83%, 3 h
25, 90%, 1.5 h
26, 58%, 1 h
28, 82%, 1.5 h
27, 64%, 1 h
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Cl
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N
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F
32, 80%, 0.5 h
34, 90%, 1.5 h
30, 73%, 1 h
33, 96%, 1 h
31, 86%, 1 h
I
F
N
N
F
B
F
36, 93%, 1.5 h
37, 60%, 0.5 h
39, 66%, 2 h
38, 62%, 3 h
35, 79%, 0.25 h
44, 93%, 0.5 h
43, 65%, 0.5 h
42, 97%, 0.75 h
41, ꢀ
40, 88%, 1 h
45, 94%, 1 h
46, 85%, 2.5 h
47, ꢀ
a Isolated yields. 1a or 1b (1 equiv), boronic acid (3 equiv), CuTC (3 equiv), Pd2(dba)3
(2.5 mol%), TFP (7.5 mol%), THF (3 mL).
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Similarly to the results observed in our first contributions,19,23b the LS crossꢀcoupling
reaction of the Biellmann BODIPYs 1a,b with a greater variety of arylꢀ and
heteroarylboronic acids continued giving excellent results. The electronic nature of the
arylboronic acids does not affect either the reaction time or the chemical yields.
Arylboronic acids with either electronꢀreleasing or electronꢀwithdrawing groups react
very smoothly to produce the expected products in good yields. Sterically demanding
boronic acids efficiently reacted as well (28, 34, 37, 38, 39, 43, 44, 45). Arylboronic
acids with reactive functional groups smoothly reacted to produce the desired products,
i.e., compounds 32, 33 and 45 without having to protect them. Heteroarylboronic acids
that are known to protodeboronate under Suzuki conditions,29 reacted efficiently under
the neutral LS crossꢀcoupling reaction conditions to yield compounds 15, 16, 37, 39, and
46 in good yields and short reaction times. The family of halogenꢀcontaining BODIPYs
initially reported (10, 11, 12, and 22) was now extended to analogues that contain Br, I
and Cl with different substitution patterns that could be further elaborated via transitionꢀ
metal catalyzed reactions (26, 27, 28, 29, 31, and 38). Of particular interest is the
straightforward preparation the formylaryl derivatives 40 and 44 in 88 and 93% yield,
respectively. If one wanted to prepare 40 using the traditional Lindsey method, several
steps involving protections and deprotections would be needed30 (Scheme 2). On the
other hand, the same compound could be prepared in a single and efficient operation via
the LꢀS crossꢀcoupling.
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SCHEME 2. Synthesis of 40 using the Lindsey method.
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O
O
CHO
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O
O
1) Pyrrole, H+
2) DDQ
CHO
CHO
deprotection
monoprotection
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N
N
F
N
N
B
B
3) BF3 OEt2, TEA
F
CHO
F
F
Compound 44, however, would be lengthy at best to prepare using the Lindsey method
because it would imply the monoprotection of 4ꢀmethoxyꢀisophthalaldehyde (eq 1) with
its inherent regioselectivity issues.
The numerous examples of commercially available formylꢀcontaining arylboronic acids
allows for the preparation of as many BODIPY derivatives and their possible applications
in areas such as dyeꢀsensitized solar cells,29c the construction of energy transfer
cassettes,29b and cysteine and homocysteine sensors.31 4ꢀAminomethylphenylboronic acid
failed to yield the desired product 47, presumably because the nucleophilic amino group
displaced the MeS group in 1a faster than the LꢀS reaction took place.24 This drawback
was not observed in the case of 3ꢀaminophenylboronic acid to give 25 due to the reduced
nucleophilicity of the nitrogen atom in aromatic amines. A similar phenomenon may
have taken place to prevent the formation of 41. We recently reported the fast transꢀ
thiolation of 1a in the presence of arylthiols in THF.32
LꢀS CrossꢀCouplings Under Microwave Irradiation. We then decided to explore the
efficiency of the microwave irradiation. Thus, a short survey was carried out (Table 1).
Table 1. LꢀS CrossꢀCouplings with Boronic Acids Under Microwave Irradiation
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% yielda
ꢀw heating
Entry
Ar
Time
Time
% yield
thermal
heating
Cmpd
1
2
3
5 min
30 min
20 min
95
1 h
70 minb
1 h
96
83b
86
33
12
31
85
90
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5
10 min
5 min
92
91
5 hb
79b
76b
4
8
30 minb
a Isolated yields. 1a (1 equiv), boronic acid (3 equiv), CuTC (3 equiv), Pd2(dba)3 (2.5
mol%), TFP (7.5 mol%), THF (3 mL) in a sealed vessel.
b Data taken from ref. 18.
Table 1 shows that the LꢀS crossꢀcoupling reaction is quite compatible with the
microwave heating regime. In all the cases studied, the reaction times shortened
significantly. Although the yields in entries 1 and two remained the same, those of entries
3ꢀ5 increased. Overall, carrying out the LꢀS coupling under microwave heating proved
advantageous.
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CrossꢀCouplings with Organostannanes. Since organostannanes also participate in the
LꢀS crossꢀcoupling,33 it was decided to compare their reactivity against that observed
with boronic acids.
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Initial testing of the typical LꢀS reaction conditions (Pd2(dba)3, TFP, Cu(I)TC, THF, 55
°C) for the coupling of 1a with organostannanes, led to incomplete conversions even
after 3 days. One attempt to accelerate the reaction in the presence of one equivalent of
CsF34 failed, only decomposition of 1a was observed. The catalytic system was changed
to Pd(PPh3)4, which resulted in a rather complex reaction mixture. We then decided to
use the conditions reported by Guillaumet et al.35 for similar reactions. The results are
shown in Table 2.
Table 2. Survey of the Reactivity of Organostannanes in the LiebeskindꢀSrogl
CrossꢀCoupling Using the Guillaumet Conditions.
% yielda
Entry
Ar
time (h)
49
Compd.
1
2
3
p-CH3OC6H4ꢀ
p-CH3C6H4ꢀ
p-ClC6H4ꢀ
O
52
75
79
8
36
31
50
22
4
5
52
46
52
52
48
2
O
C6H5ꢀ
a Isolated yield. BODIPY 1a (1 equiv), ArSnBu3 (3 equiv), CuBr•SMe2 (3 equiv),
Pd(PPh3)4 (5 mol%), THF (5 mL).
Although the products were obtained in moderate to good yields, the reactions in all of
the cases analyzed were very sluggish taking up to 50 h to go to completion.
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Since the results were not quite satisfactory, we turned our attention to studying the
outcome of the reaction using copper (I) diphenylphosphinate, Cu(I)OP(O)Ph2, as the Cu
source, since it has been demonstrated that it gives good results in similar crossꢀcoupling
with organostannanes.33a The results are shown in Table 3.
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Table 3. Survey of the Reactivity of Organostannanes in the LiebeskindꢀSrogl
CrossꢀCoupling Using Cu(I) Phosphinate as Cu(I) Source.
% yielda
Entry
Ar
time (h)
1.0
Compd.
1
2
3
p-CH3OC6H4ꢀ
p-CH3C6H4ꢀ
p-ClC6H4ꢀ
O
85
77
81
8
36
31
0.5
0.5
4
5
0.5
0.5
75
90
48
2
O
C6H5ꢀ
a Isolated yield. BODIPY 1a (1 equiv), ArSnBu3 (3 equiv), CuOP(O)Ph2 (3 equiv),
Pd(PPh3)4 (5 mol%), THF (3 mL).
Gratifyingly, the reaction times in all cases surveyed dropped to one hour or less and the
yields increased significantly irrespective of the electronic properties of the aryl groups,
at least in the group studied.
Photophysical properties. The spectroscopic properties of selected mesoꢀ
(het)arylBODIPY derivatives listed in Chart 1 and 2 are collected in Table 4.
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Table 4. Photophysical Properties of Selected BODIPYs in tetrahydrofurane;
absorption (λab) and fluorescence (λfl) wavelengths, and fluorescence quantum yield
(Φ). The complete photophysical data of compounds listed in Chart 2 are collected
in Table S1 in ESI.
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%Φa
Cmpd
Cmpd
λab
(nm)
501
499
373, 502
493
λfl
(nm)
520
520
524
532
527
524
520
533
527
529
527
533, 622
ꢀ
%Φ
λab
(nm)
514
518
502
500
502
514
499
516
512
500
517
508
520
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512
502
505
500
514
λfl
(nm)
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522
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521
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541
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ꢀ
2.6
1.1
1.0
5.3
0.4
2.4
3.5
0.7
1.1
1.3
29.5
2.3
ꢀ
2.9
ꢀ
13.5
0.6
ꢀ
0.5
0.3
1.3
6.3
55.0
0.7
1.0
0.7
2.9
1.5
25.0
5.2
3.6
2
3
4
5
6
7
8
9
10
11
12
13
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25
26
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30
31
32
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34
35
36
37
38
39
40
42
43
44
45
46
502
501
498
494
502
504
507
505
55.4
8.7
35.0
1.7
506
510
620
583
525
524
530
539
526
522
417, 520
507
387, 501
503
9.7
51.0
43.0
87.8
ꢀ
506
511
502
a Concentration: 20 ꢀM
The presence of a phenyl ring at meso position of the BODIPY 2 has little impact in the
absorption spectra due to the absence of resonance interaction. In fact, the 8ꢀphenyl group
does not contribute to the electronic density of the frontier molecular orbitals involved in
the electronic transition.17 Moreover, the functionalization of such ring scarcely shifts the
absorption band (centered around 500ꢀ505 nm, Table 4), although electron donors (i.e.,
amine in 9 and methoxy in 3 and 8) or acceptors (i.e., halogens in 10ꢀ12 or 29 and
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carboxylates in 32 and 43) have been grafted to different positions of the 8ꢀphenyl. Just a
slight bathochromic shift (10ꢀ15 nm, Table 4) is recorded in the absorption band owing to
the direct attachment of electron donor heteroaryls (thiophene in 15 and 46 or furane in
16) to the meso position of the BODIPY, which might indicate some degree of electron
coupling with the cyanineꢀlike delocalization of the chromophoric core. Overall,
absorption bands at lower energies (centered around 510ꢀ520 nm, Table 4) are recorded
for the diethylated compounds in the 3 and 5 positions (see compounds 25ꢀ28, 32, 34, 35,
37, 39, 40, 42 and 46 form Chart 2) due to the positive inductive effect of the alkyl
groups especially in those chomophoric αꢀpositions, as will be emphasized later.
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Nonetheless, the arylation of the meso position plays a fundamental role in the emission
signatures (mainly in the fluorescence efficiency) of the herein attained compounds
(Table 4). As a matter of fact, those compounds in which the aryl ring can easily rotate
due to the lack of substituents at neither adjacent 1 and 7 positions of the BODIPY core
nor at the ortho positions of the 8ꢀaryl moiety (compounds 2ꢀ20, except 12 and 17 from
Chart 1, and 25ꢀ27, 29ꢀ33, 35ꢀ36, 40, 42 and 46 from Chart 2) are characterized by very
low fluorescence efficiency (< 10%, Table 4). The rotational motion of the aryl at meso
position greatly enhances the vibrational coupling with the BODIPY chromophore and
eventually can distort its planarity. Both factors result in an increase in the nonꢀradiative
relaxation pathways.36 The fluorescence efficiency is worsened by the additional
presence in the aryl ring of strong electron donating or withdrawing groups which enable
fluorescenceꢀquenching intramolecular charge transfer (ICT) processes. For instance, the
emission becomes almost negligible in compounds 14 and 25 (Table 4), both of them
bearing electron releasing groups (ferrocene and amino, respectively) which are known to
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be capable of promoting such kind of phenomena. Moreover, in derivatives 13, 15 and 16
even a weak emission from the ICT is detected at long wavelengths, especially with
pyrene and thiophene, as it is show in Figure 2. Indeed, in compound 13 a dual emission
is clearly detected; the fluorescence from the locally excited (LE) state and the
fluorescence from the ICT state, which is populated from such LE (Figure 2). The
replacement of pyrene by the more electron donor thiophene (15) leads to the complete
quenching of the emission from the LE, and just the long wavelength emission from the
ICT is detected, albeit quite weak. It is noteworthy that such redꢀshifted emission
recorded for compound 15 is not longer detected when a phenyl ring is fused to the 8ꢀ
thiophene 46, which results in a completely loss of the fluorescence signal. Likely, the
charge separation is further favoured increasing the nonꢀradiative deactivation from the
ICT state.
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Figure 2. Fluorescence spectra of compounds 2 (8ꢀphenyl), 13 (8ꢀpyrene) and 15 (8ꢀ
thiophene).
As stated above, ethylation at the key chromophoric αꢀpositions not only
bathochromically shifts the spectral bands, but also counteracts in part the above
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commented internal conversion promoted by the unconstrained 8ꢀaryl groups. Thus,
comparing the analogs bearing the trimethylsilyl group (30 vs 42) an improvement in the
fluorescence efficiency is attained upon alkylation (from 1% to 9.7% respectively, Table
4). The same trend is nicely observed in the BODIPYs bearing brominated phenyls at
different positions (non alkylated 10, 11 and 12 vs 26, 27 and 28 ethylated at positions 3
and 5). Such improvement is attributed to an enhancement in the electronic delocalization
by the insertion of inductive electron donor alkyl groups at the αꢀpositions of the cyanine
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πꢀsystem.36 In fact the highest molar absorption coefficients (around 90000ꢀ 100000 Mꢀ1
cmꢀ1 in Table S1 in ESI) are calculated for alkylated compounds (i.e., 25, 27, 35 and 42).
In contrast, the ortho substitution of the aryl ring reverses the situation and bright
BODIPYs are attained (Table 4). Figure 3 shows that whereas for the aforementioned
derivatives with unconstrained 8ꢀaryl and hence low fluorescence quantum yields, the
lifetimes were very fast (multiexponentials with main lifetime below 1 ns, see Figure 3
and Table 1 in ESI), the steric hindrance provided by the ortho substitution not only
raises up the fluorescence efficiency but also lengthens the lifetime (monoexponentials
with values around 3ꢀ6 ns, those typical of BODIPY, see Figure 3 and Table 1 in ESI)
owing to the restriction of the aryl free motion. Indeed, among the compounds in Chart 1,
the highest fluorescence quantum yield is recorded for compound 12 (29.5% in Table 4)
bearing an orthoꢀbrominated 8ꢀphenyl fragment, while its brominated analogs at para or
meta positions (10 and 11, respectively) show much more reduced fluorescence
efficiencies (1.1% and 1.3%, Table 4). Nicely, the selective bromination of the phenyl
ring leads to the same trend in derivatives 26ꢀ28 from Chart 2, but with ameliorated
fluorescence efficiencies due to the aforementioned alkylation effect. Moreover, in Chart
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2 all the ortho substituted derivatives (34, 37ꢀ39 and 43ꢀ45) provide the highest
fluorescence efficiencies, which reach values as high as 87.8% for compound 45 (Table
4), and longer lifetimes (grey shaded in Figure 3).
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Figure 3. Fluorescence lifetime of selected BODIPY listed in Chart 2 with orthoꢀ
susbtitution (grey) and without substitution (white) at such position of the 8ꢀaryl.
For the last set of compound the main lifetime (contribution > 98%) is provided due
to the biexponential deconvolution of the decay curve.
All this background prompted us to analyzed the rotational barrier of the 8ꢀphenyl in
BODIPYs where is motion is readily free (compound 31 was chosen as representative) or
progressively hindered by steric hindrance due to the ortho substitution of the aryl groups
(38 and 45, those with the smallest and highest fluorescence efficiency among these kind
of derivatives). Such theoretical potential energy surface was computed scanning and
relaxing the energy with regard to the dihedral angle between the phenyl and the indacene
core planes using Molecular Mechanics (MM2) (some representative curves are depicted
in Figure 4) and the Density Functional method (DFT, in particular B3LYP, see
experimental section for further details). As expected, the lowest rotational barrier is
calculated for compound 31 (13.2 kcal/mol by MM2, Figure 4, and 10.0 kcal/mol by
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DFT), where the most stable conformation is with the phenyl ring twisted around 52º
with respect to the indacene core.. The presence of a fluorine atom at ortho position in 38
hinders the phenyl motion as reflected in a higher rotational barrier (18.6 kcal/mol by
MM2, Figure 4, and 15.7 kcal/mol by DFT) and a higher twisting angle (60º). However,
owing to its small size the steric hindrance seems not to be high because its fluorescence
efficiency is still low (8.7%, Table 4). Further evidence is provided by compound 12
bearing an orthoꢀbromine. Its larger size should induce a higher steric hindrance to the
phenyl motion, reflected in a higher rotational barrier (28.1 kcal/mol by MM2 and 25.1
kcal/mol by DFT) and a more twisted 8ꢀphenyl (65º), which leads to an improved
fluorescence signal (29.5% Table 4). In line with this argument, compound 45 shows a
larger rotational barrier (around 35 kcal/mol by MM2 and 37.6 by DFT) and a more
perpendicular disposition (phenyl twisted 70º). Thus, the geometrical constraint provided
by the hidroxymethylene seems to be high enough to lock the phenyl ring motion,
thereby giving rise to very high fluorescence efficiencies (up to 87.8%, Table 4). Alike
energy values have been reported for the rotational barrier of structural related 8ꢀarylꢀ
BODIPYs.37 It is noteworthy that the lowꢀdemanding (from a computationally point of
view) and fast MM2 method, describes qualitatively way the evolution of the rotational
barrier with regard to the steric hindrance induced by the ortho substitution, although the
energy values deviate around 3 kcal/mol (usually MM2 overestimates the barrier) with
regard to the more accurate DFT method.
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Figure 4. Energy potential surface with regard to the rotation of the 8ꢀaryl fragment
by MM2 method for representative compounds 31 and 38.
Therefore, constrained structures are required to keep the excellent fluorescence signal
from the BODIPY. Nevertheless, those derivatives bearing 8ꢀaryl with free motion are
being applied in the emerging field of molecular rotors to monitor the environmental
viscosity owing to the sensibility of both the fluorescence efficiency and lifetime to the
ring rotation.38 The herein presented set of derivatives could be applied as such kind of
probes with the additional advantage that the functionalization of the 8ꢀaryl group (i.e,
halogens, carboxylic acids) enables subsequent synthetic modification to improve for
instance the biological compatibility or to seek for a specific target.
Conclusions
A detailed study has been carried out regarding the scope and limitations of the
Biellmann BODIPY as the electrophilic partner in the LiebeskindꢀSrogl crossꢀcoupling
reaction. Several highly substituted arylꢀ and heteroarylboronic acids were tested to give
the desired products in short reaction times and good to excellent yields. The only
observed limitations were in cases where the boronic acids contained nucleophilic groups
(i.e., NH2 and SH groups) for in those cases, the reaction failed to yield the expected
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product. It was also demonstrated that the LꢀS cross coupling reaction works efficiently
using microwaves, giving the products in higher yields, or shorter reaction times, or both.
In addition to boronic acids, we showed that organostanannes were also effective partners
in the LꢀS cross coupling reaction with the Biellmann BODIPY. It is envisioned that this
methodology will be highly favored by the chemistry community interested in BODIPY
dyes due to all of the advantages it presents, as well as to the fact that Biellmann
BODIPYs are commercially available. The functionalization at the key meso position
severely alters the fluorescence signatures of the BODIPY. Bulky substituents at the
ortho position of 8ꢀaryl groups are required to provide high enough steric hindrance, as
reflected in higher rotational barriers, to lock the ring rotational motion and ensure high
fluorescence efficiencies, which can be further boosted by alkylation at positions 3 and 5.
Alternatively, the electron coupling of electron releasing groups at the 8 position of
BODIPY promotes ICT states with longꢀwavelength emission, but with the handicap of
its inherent low fluorescence efficiency.
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Experimental Section
Synthesis and characterization: All of the starting materials were purchased from
commercial sources and used without further purification. 1H and 13C NMR spectra were
recorded spectrometer in deuteriochloroform (CDCl3), with either tetramethylsilane
1
13
1
13
(TMS) (0.00 ppm H, 0.00 ppm C), or chloroform (7.26 ppm H, 77.00 ppm C), as
internal reference. Data are reported in the following order: chemical shift in ppm,
multiplicities (br (broadened), s (singlet), d (doublet), t (triplet), q (quartet), sex (sextet),
hep (heptet), m (multiplet), exch (exchangeable), app (apparent)), coupling constants, J
(Hz), and integration. Infrared peaks are reported (cmꢀ1) with the following relative
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intensities: s (strong, 67–100 %), m (medium, 40–67%), and w (weak, 20–40%). HRMS
were recorded as specified. Melting points were determined on the appropriate equipment
and are not corrected. TLC was conducted in Silica gel on TLC Al foils. Detection was
done by UV light (254 or 365 nm). The reactions with microwave heating were carried
out on a CEM Discover SP reactor with a vertical IR focalized internal temperature
sensor. Mass spectrometry data were collected on a TOF analyzer.
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Spectroscopic measurements. The photophysical properties were registered in diluted
solutions (around 2×10ꢀ6 M) of tetahydrofurane, using quartz cuvettes with optical
pathway of 1 cm. UVꢀVis absorption and fluorescence spectra were recorded on a
spectrophotometer and a spectrofluorimeter, respectively. Fluorescence quantum yield
(Φ) was obtained by using a suitable commercial BODIPY as reference (PM567 in
methanol Φ = 0.91). Radiative decay curves were registered with the time correlated
singleꢀphoton counting technique , equipped with a microchannel plate detector of
picosecond timeꢀresolution (20 ps). Fluorescence emission was monitored at the
maximum emission wavelength after excitation at 470 nm by means of a diode laser with
150 ps FWHM pulses. The fluorescence lifetime (τ) was obtained after the deconvolution
of the instrumental response signal from the recorded decay curves by means of an
iterative method. The goodness of the exponential fit was controlled by statistical
parameters (chiꢀsquare, DurbinꢀWatson and the analysis of the residuals). The amplitude
average lifetime was calculated by means of : <τ>aa = ΣAi·τi
Computational modeling. Ground state energy minimizations were performed using the
Becke´s Three Paramaters (B3LYP) Density Functional (DFT) method. The basis set was
the double valence 6ꢀ31g, except from those compounds bearing iodine (i.e., 38) where
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the lanl2dz basis set, especially parameterized for such heavy atoms, was considered. The
optimized geometry was taken as an energy minimum using frequency calculations (no
negative frequencies). Rotational energy barriers were calculated from the potential
energy surface, which was simulated by relaxed scans of the 8ꢀphenyl twist with regard
to the plane of the BODIPY core. Two complementary approaches were considered to
this aim. First, the relaxed scans were carried out using the MM2 force field as
implemented in ChemBio 3D Ultra (ChemBioOffice 2014 software). The resolution of
the scan was 1º. Finally, the potential surface was simulated by the B3LYP method
computing and minimizing the energy in steps of 10º. The solvent effect
(tetrahydrofuran) was considered in the DFT calculations by the Polarizable Continuum
Model (PCM), except for compound 38, where the calculations were done at gas phase,
since the iodine atom is not parameterized in PCM. All the DFT calculations were
performed in Gaussian 09, using the “arina” computational resources provided by the
UPVꢀEHU.
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General procedure for the LꢀS crossꢀcoupling with boronic acids (GP1). A
Schlenk tube equipped with a stir bar was charged with a either 1a or 1b (1 equiv), the
corresponding boronic acid (3 equiv), and dry THF (3 mL). The mixture was sparged
with N2 for 5 min whereupon Pd2(dba)3 (2.5 mol%), trifurylphosphine (7.5%), and CuTC
(3 equiv) were added under N2. The Schlenk tube was then and immersed in a preꢀheated
oilꢀbath at 55 °C. The oilꢀbath was removed after the starting BODIPY was consumed
(TLC, 20% EtOAc/hexanes) (see Chart 2 for reaction times). After the mixture reached
rt, the crude material was adsorbed in SiO2ꢀgel and the product was purified by flash
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chromatography on SiO2ꢀgel using EtOAc/hexanes gradients. For purposes of
characterization, the products were crystallized from CH2Cl2/petroleum ether.
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BODIPY 25. According to GP1. 1b (30.0 mg, 0.102 mmol), 3ꢀaminophenylꢀ
boronic acid (47.4 mg, 0.306 mmol), Pd2(dba)3 (2.4 mg, 2.6 x10ꢀ3 mmol), TFP (1.8 mg,
7.6 x10ꢀ3 mmol) and CuTC (58.3 mg, 0.306 mmol). The desired product (26.2 mg, 90%)
mmol) was obtained as orange crystals. TLC (30% EtOAc/hexanes, Rf = 0.46); mp 176ꢀ
177 °C; IR (KBr, cm-1): 3495 (m), 3466 (m), 3399 (m), 3377 (m), 2927 (m),
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1556 (s), 1432 (s), 1284 (s), 1150 (s), 1031 (s), 998 (s), 950 (s), 800
1
(s); H NMR (200 MHz, CDCl3): δ 7.21 (d, J = 8.0 Hz, 2H), 6.89ꢀ6.80 (m, 4H), 6.33 (d,
J = 4 Hz, 2H), 3.79 (bs, 2H), 3.07 (q, J = 8.0 Hz, 4H) 1.34 (t, J = 8.0 Hz, 6H); 13C NMR
(50 MHz, CDCl3): δ 163.3, 146.1, 143.2, 135.2, 134.2, 130.5, 129.0, 120.9, 117.1, 116.7,
116.4, 22.0, 12.8. HRMS FABS (M+H+) Calcd for C19H21BF2N3: 340.1796. Found:
340.1799.
BODIPY 26. According to GP1. 1b (30.0 mg, 0.102 mmol), pꢀ
bromophenylboronic acid (62.0 mg, 0.306 mmol), Pd2(dba)3 (2.4 mg, 2.6 x10ꢀ3 mmol),
TFP (1.8 mg, 7.6 x10ꢀ3 mmol), and CuTC (58.3 mg, 0.306 mmol). The desired product
(23.4 mg, 58%) was obtained as red crystals. TLC (15% EtOAc/hexanes, Rf = 0.64); mp
135ꢀ136 °C; IR (KBr, cmꢀ1): 2977 (w), 2941 (w), 1571 (s), 1554 (s), 1488 (s), 1437 (s),
1322 (s), 1257 (s), 1220 (m), 1129 (s), 1070 (m), 1051 (s), 1009 (s), 980 (s), 883 (m), 803
1
(m), 758 (m), 733 (m); H NMR (200 MHz, CDCl3): δ 7.63 (dd, J1= 6.4 Hz, J2= 2.0 Hz,
2H), 7.37 (dd, J1= 6.6 Hz, J2= 2.0 Hz, 2H), 6.70 (d, J = 4.4 Hz, 2H), 6.36 (d, J = 4.2 Hz,
2H), 3.07 (q, J = 7.6 Hz, 4H), 1.34 (t, J = 7.6, 6H); 13C NMR (50 MHz, CDCl3): δ 164.3,
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141.4, 134.2, 133.3, 132.0, 131.7, 130.4, 124.6, 117.8, 22.3, 12.9. HRMS FABS (M+H+)
Calcd for C19H19BBrF2N2: 403.0793. Found: 403.0797.
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BODIPY 27. According to GP1. 1b (20.0 mg, 0.068 mmol), 3ꢀ
bromophenylboronic acid (50.0 mg, 0.204 mmol), Pd2(dba)3 (1.5 mg, 1.7x10ꢀ3 mmol),
TFP (1.2 mg, 5.0x10ꢀ3 mmol), and CuTC (38.8 mg, 0.204 mmol). T he desired product
(17.5 mg, 64%) was obtained as an orange solid. TLC (15% EtOAc/hexanes, Rf = 0.62);
mp 124ꢀ126 °C; IR (KBr, cmꢀ1): 2968 (w), 2939 (w), 1574 (s), 1550 (s), 1488 (s), 1432
(s), 1342 (m), 1320 (s), 1280 (s), 1152 (s), 1139 (s), 1089 (m), 1058 (m), 1039 (s), 985
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(s), 899 (m), 798 (m), 761 (m), 733 (m), 720 (m); H NMR (200 MHz, CDCl3): δ 7.69ꢀ
7.650 (m, 2H), 7.46ꢀ7.27 (m, 2H), 6.73 (d, J = 4.4 Hz, 2H), 6.37 (d, J = 4.2 Hz, 2H), 3.09
13
(q, J = 7.5 Hz, 4H), 1.35 (t, J = 7.6, 6H); C NMR (50 MHz, CDCl3): δ 164.4, 140.8,
136.3, 134.2, 133.1, 133.1, 130.4, 129.9, 129.1, 122.5, 117.9 22.3, 12.9. HRMS FABS
(M+H+) Calcd for C19H19BBrF2N2: 403.0793. Found: 403.0798.
BODIPY 28. According to GP1. 1b (17.8 mg, 0.066 mmol), o-
bromophenylboronic acid (39.7 mg, 0.198 mmol), Pd2(dba)3 (1.5 mg, 1.6x10ꢀ3 mmol),
TFP (1.1 mg, 4.9x10ꢀ3 mmol), and CuTC (37.6 mg, 0.198 mmol). The product (20.0 mg,
82%) was obtained as red crystals. TLC (15 % EtOAc/hexanes, Rf = 0.52); mp 111ꢀ113
°C; IR (KBr, cmꢀ1): 3118 (w), 3063 (w), 2979 (w), 2961 (w), 2932 (w), 2872 (w), 1566
(s), 1555 (s), 1490 (m), 1462 (m), 1435 (m), 1345 (w), 1309 (m), 1284 (s), 1212 (w),
1140 (s), 1212 (w), 1140 (s), 1087 (m), 1025 (s), 1000 (s), 982 (s), 885 (w), 796 (m), 746
(m), 736 (m), 704 (w); 1H NMR (400 MHz, CDCl3) δ 7.69 (d, J = 7.7 Hz, 1H), 7.45 –
7.31 (m, 3H), 6.52 (d, J = 4.2 Hz, 2H), 6.32 (d, J = 4.2 Hz, 2H), 3.08 (q, J = 7.6 Hz, 4H),
1.35 (t, J = 7.6 Hz, 6H). 13C NMR (100 MHz, CDCl3) δ 165.0, 140.8, 135.5, 134.8,
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133.5, 132.0, 131.1, 130.2, 127.2, 123.5, 117.9, 117.8, 21.3, 12.3. HRMS FABS (M+H+)
Calcd for C19H19BBrF2N2: 403.0793. Found: 403.0798.
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BODIPY 29. According to GP1. 1a (20.0 mg, 0.084 mmol), pꢀiodophenylboronic
acid (62.5 mg, 0.252 mmol), Pd2(dba)3 (1.9 mg, 2.1 x10ꢀ3 mmol), TFP (1.6 mg, 6.3 x10ꢀ3
mmol), and CuTC (48 mg, 0.252 mmol). The desired product (27.1 mg, 83%) was
obtained as an orange solid. TLC (30% EtOAc/hexanes, Rf = 0.45); mp 193ꢀ195 °C; IR
(KBr, cmꢀ1): 3106 (w), 1563 (s), 1538 (s), 1478 (m), 1414 (s), 1395 (s), 1260 (s), 1224
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(m), 1155 (m), 1116 (s), 1082 (s), 976 (m), 908 (m), 774 (m), 739 (m) H NMR (200
MHz, CDCl3): δ 7.95(s, 2H), 7.89(d, J = 8.4 Hz, 2H), 7.30 (d, J = 8.4 Hz, 2H), 6.91 (d, J
= 3.6 Hz, 2H), 6.56 (d, J = 3.6 Hz, 2H); 13C NMR (50 MHz, CDCl3): δ 144.7, 137.9,
134.7, 133.3, 132.0, 131.47, 119.0, 118.94, 97.64. HRMS FABS (M+H+) Calcd for
C15H11BF2IN2: 395.0028. Found: 395.0021.
BODIPY 30. According to GP1. 1a (50.0 mg, 0.210 mmol), 4ꢀ
(trimethylsilyl)phenylboronic acid (122.0 mg, 0.630 mmol), Pd2(dba)3 (4.8 mg, 5.2x10ꢀ3
mmol), TFP (3.6 mg, 1.6x10ꢀ3 mmol), and CuTC (119.7 mg, 0.630 mmol). The desired
product (52.4 mg, 73%) was obtained as an orange solid. TLC (30% EtOAc/hexanes, Rf
1
= 0.83); mp 158ꢀ159 °C; H NMR (400 MHz, CDCl3) δ 7.95 (s, 2H), 7.61 (dd, J = 49.5,
8.0 Hz, 4H), 6.97 (d, J = 4.1 Hz, 2H), 6.55 (d, J = 3.2 Hz, 2H), 0.34 (s, 9H).39
BODIPY 31.
According to GP1. 1a (10.0 mg, 0.042 mmol), 4ꢀ
chlorophenylboronic acid (19.7 mg, 0.126 mmol), Pd2(dba)3 (1.0 mg, 1.0 x10ꢀ3 mmol),
TFP (0.7 mg, 1.0 x10ꢀ3 mmol) and CuTC (23.9 mg, 0.126 mmol). The desired product
(10.9 mg, 86%) was obtained as an orangeꢀreddish solid. TLC (15% AcOEt/Hexanes Rf =
0.36)
;
mp= 199ꢀ200 °C; IR (KBr, cmꢀ1): 3134 (w), 3107 (w), 1572 (s), 1543 (s), 1413 (s),
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1401 (s), 1384 (s), 1260 (s), 1155 (m), 1116 (s), 1081 (s), 1049 (m), 979 (m).1H NMR
(200 MHz, CDCl3) δ 7.96 (s, 2H), 7.51 (s, 4H), 6.92ꢀ6.90 (m, 2H), 6.57ꢀ6.55 (m, 2H);
13C NMR (50 MHz, CDCl3) δ 145.9, 144.7, 137.5, 134.9, 132.4, 131.9, 131.5, 129.1,
119.0. HRMS FABS (M+H+) Calcd for C15H11BClF2N2: 303.0672. Found: 303.0674.
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60
BODIPY 32.
According to GP1. 1b (40 mg, 0.136 mmol), 4ꢀ
carboxyphenylboronic acid (68.0 mg, 0.408 mmol), Pd2(dba)3 (3.0 mg, 3.4x10ꢀ3 mmol),
TFP (3.0 mg, 0.011 mmol) and CuTC (78.0 mg, 0.411 mmol). The desired product (40
mg, 80%) was obtained as a red solid. TLC (15% EtOAc/hexanes, Rf = 0.33); mp 202ꢀ
203 °C; IR (KBr, cmꢀ1): 2974 (m), 1710 (s), 1575 (s), 1555 (s), 1438 (s), 1275 (s), 1140
1
(s), 1034 (m), 886 (w), 801 (w), 723 (m), 541 (m); H NMR (200 MHz, CDCl3): δ 8.23
(d, J= 8.0 Hz, 2H), 7.62 (d, J= 8.0 Hz, 2H), 6.70 (d, J= 4.0 Hz, 2H), 3.07 (q, J= 7.0 Hz,
4H), 1.35 (t, J= 7.5 Hz, 6H); 13C NMR (50 MHz, (CD3)2CO/CD3SO, 3:1): δ 164.2, 142.8,
138.3, 135.0, 134.3, 132.9, 132.6, 131.2, 129.2, 118.6, 22.6, 13.3. HRMS FABS (M+H+)
Calcd for C20H20BF2N2O2: 369.1586. Found: 369.1589.
BODIPY 33.
According to GP1. 1a (50.0 mg, 0.210 mmol), 3ꢀ
(hydroxymethyl)phenylboronic acid (95.7 mg, 0.630 mmol), Pd2(dba)3 (5.0 mg, 5.3 x10ꢀ3
mmol), TFP (3.7 mg, 1.6 x10ꢀ3 mmol) and CuTC (119.7 mg, 0.630 mmol). The desired
product (60.1 mg, 96%) was obtained as a red solid. TLC (30% EtOAc/hexanes, Rf =
0.17 ); mp 121ꢀ123 °C; IR (KBr, cmꢀ1): 3400 (s), 2892 (m), 1545 (s), 1476 (m), 1414 (s),
1389 (s), 1260 (s), 1190 (m), 1116 (s), 1081 (s), 991 (m), 775 (m), 736 (m), 607 (w), 583
1
(w); H NMR (500 MHz, CDCl3) δ 7.95 (s, 2H), 7.55 (ddd, J = 21.0, 14.1, 7.5 Hz, 4H),
6.93 (d, J = 3.7 Hz, 2H), 6.55 (d, J = 3.0 Hz, 2H), 4.82 (s, 2H). 13C NMR (75 MHz,
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CDCl3): δ 147.5, 144.5, 141.7, 134.3, 131.9, 129.9, 129.4, 129.0, 128.9, 118.8, 64.9.
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6
7
HRMS FABS (M+H+) Calcd for C16H14BF2N2O: 299.1167. Found: 299.1160.
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BODIPY 34.
According to GP1. 1b (25.0 mg, 0.085 mmol) and 2ꢀ
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biphenylboronic acid (50.0 mg, 0.255 mmol), Pd2(dba)3 (1.0 mg, 2.1x10ꢀ3 mmol), TFP
(1.0 mg, 6.3x10ꢀ3 mmol) and CuTC (48.0 mg, 0.2550 mmol). The desired product (32.0
mg, 90%) was obtained as orange crystals. TLC (15% EtOAc/hexanes, Rf = 0.48); mp
145ꢀ147 °C; IR (KBr, cmꢀ1): 2929 (w), 1566 (s), 1554 (s), 1488 (w), 1434 (w), 1314 (m),
1
1287 (m), 1140 (s), 1127 (s), 1021 (s), 1002 (s), 982 (m), 746 (m), 720 (w),700 (w); H
RMN (200 MHz, CDCl3): δ 7.55ꢀ7.54 (m, 2H), 7.44ꢀ7.42 (m, 2H), 7.26ꢀ7.19 (m, 5H),
6.54 (d, J= 4.0 Hz, 2H), 6.19 (d, J= 4.4 Hz, 2H), 3.03ꢀ2.97 (m, 4H), 1.28 (t, J= 7.4 Hz,
6H); 13C RMN (50 MHz, CDCl3): δ 163.2, 142.3, 141.9, 140.4, 134.9, 132.6, 131.5,
130.5, 130.2, 129.7, 128.6, 128.4, 127.3, 126.7, 117.1, 22.0, 12.6. HRMS FABS (M+H+)
Calcd for C25H24BF2N2: 401.2001. Found: 401.2005.
BODIPY 35. According to GP1. 1b (10.0 mg, 0.034 mmol), 6ꢀmethoxyꢀ2ꢀ
naphthaleneboronic acid (20.6 mg, 0.102 mmol), Pd2(dba)3 (0.8 mg, 8.5x10ꢀ4 mmol), TFP
(0.6 mg, 2.5x10ꢀ3 mmol), and CuTC (19.4 mg, 0.102 mmol). The desired product (10.8
mg, 79%) was obtained as an orange solid. TLC (20% EtOAc/hexanes, Rf = 0.54); mp
185ꢀ187 °C; IR (KBr, cmꢀ1): 2973 (w), 1626 (m), 1556 (s), 1491 (s), 1438 (s), 1390 (m),
1319 (s), 1272 (s), 1203 (s), 1147 (s), 1075 (m), 1031(s), 1009 (s), 987 (s); 1H NMR (200
MHz, CDCl3): δ 7.92 (s, 1H), 7.81 (dd, J1= 7.8 Hz, J2= 2.6 Hz, 2H), 7.57 (dd, J1= 8.4 Hz,
J2= 1.6 Hz, 1H), 7.21 (s, 2H), 6.79 (d, J= 4.0 Hz, 2H), 6.36 (d, J= 4.2 Hz, 2H), 3.97 (s,
3H), 3.09 (q, J= 7.8 Hz, 4H), 1.35 (t, J= 7.6 Hz, 6H); 13C NMR (50 MHz, CDCl3): δ
163.5, 159.1, 143.4, 135.5, 134.7, 130.8, 130.4, 130.3, 129.8, 128.5, 128.3, 126.8, 120.1,
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117.4, 105.9, 55.7, 22.3, 13.0. HRMS FABS (M+H+) Calcd for C24H24BF2N2O:
405.1950. Found: 405.1954.
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BODIPY 36. According to GP1. 1a (100.0 mg, 0.420 mmol), pꢀtolylboronic acid
(171.3 mg, 1.260 mmol), Pd2(dba)3 (9.6 mg, 0.011 mmol), TFP (7.3 mg, 0.032 mmol)
and CuTC (240.3mg, 1.260 mmol). The desired product (111.1 mg, 93%) was obtained
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as orange crystals. H NMR (200 MHz, CDCl3) δ 7.93 (s, 2H), 7.48 (d, J = 8 Hz, 2H),
7.33 (d, J = 8 Hz, 2H), 6.95 (d, J = 4.2 Hz, 2H), 6.54 (d, J = 3.2 Hz, 2H), 2.48 (s, 3H).40
BODIPY 37.
According to GP1. 1b (20.0 mg, 0.068 mmol) and 1ꢀ
(phenylsulfonyl)ꢀ2ꢀindolylboronic acid (61.4 mg, 0.204 mmol), Pd2(dba)3 (1.5 mg,
1.7x10ꢀ3 mmol), TFP (1.2 mg, 5.0x10ꢀ3 mmol), and CuTC (38.8 mg, 0.204 mmol). The
desired product (20.5 mg, 60%) was obtained as an orange solid. TLC (15%
AcOEt/hexanes Rf = 0.25); mp 176ꢀ178 °C; IR (KBr, cmꢀ1): 3158 (w), 3119 (w), 2974
(w), 2937 (w), 2880 (w), 1580 (s), 1559 (s), 1489 (s), 1437 (s), 1376 (s), 1322 (s), 1275
(m), 1187 (m), 1174 (m), 1140 (s), 1089 (m), 1039 (s), 1011 (m), 972 (m), 962 (m), 851
(m), 797 (m), 763 (m), 730 (s), 686 (m), 592 (s), 571 (s), 553 (m).1H NMR (200 MHz,
CDCl3) δ 8.10ꢀ7.95 (m, 3H), 7.84 (s, 1H), 7.63ꢀ7.27 (m, 6H), 6.80 (d, J= 4.2 Hz, 2H),
6.32 (d, J= 4.2 Hz, 2H), 3.09 (q, J= 7.8 Hz, 4H), 1.35 (t, J= 7.4, 6H); 13C NMR (50 MHz,
CDCl3) δ 164.2, 138.0, 135.1, 134.6, 134.2, 133.5, 130.6, 129.9, 129.8, 127.9, 127.1,
126.0, 124.3, 121.3, 117.4, 117.1, 113.9, 22.3, 13.0. HRMS FABS (M+H+) Calcd for
C27H25BF2N3O2S: 504.1729. Found: 504.1732.
BODIPY 38. According to GP1. 1a (50.0 mg, 0.210 mmol) and 2ꢀfluoroꢀ5ꢀ
iodophenylboronic acid (167.5 mg, 0.630 mmol), Pd2(dba)3 (4.8 mg, 5.2x10ꢀ3 mmol),
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TFP (3.6 mg, 1.6 x10ꢀ3 mmol), and CuTC (119.7 mg, 0.630 mmol). The desired product
(53.5 mg, 62%) was obtained as a red solid. TLC (20% EtOAc/hexanes, Rf = 0.46); mp
143ꢀ145 °C; IR (KBr, cmꢀ1): 3130 (w), 3101 (w), 1569 (s), 1547 (s), 1412 (s), 1387 (s),
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1259 (s), 1106 (s),1071 (s), 1040 (s), 986 (s); H NMR (200 MHz, CDCl3): δ 7.94 (s,
2H), 7.88ꢀ7.74 (m, 2H), 7.03 (t, J = 9.2 Hz, 1H), 6.84 (d, J = 4.0 Hz, 2H), 6.54 (d, J = 4.2
13
Hz, 2H); C NMR (50 MHz, CDCl3): δ 159.7 (d, J= 251.5 Hz), 145.6, 141.3 (d, J= 7.6
Hz), 140.3, 138.4, 135.1, 131.3, 123.9 (d, J= 15.9 Hz), 119.3, 118.7 (d, J= 22.7 Hz), 86.9
(d, J= 3.8 Hz). HRMS FABS (M+H+) Calcd for C15H10BF3IN2: 412.9934. Found:
412.9933.
BODIPY 39. According to GP1. 1b (25.0 mg, 0.085 mmol) and 1ꢀNꢀBocꢀ
pyrroleꢀ2ꢀboronic acid (53.0 mg, 0.255 mmol), Pd2(dba)3 (1.0 mg, 2.1x10ꢀ3 mmol), TFP
(1.0 mg, 6.3x10ꢀ3 mmol), and CuTC (48.0 mg, 0.255 mmol). The desired product (25 mg,
66%) was obtained as red crystals. TLC (15% EtOAc/hexanes, Rf = 0.56); mp 130ꢀ132
°C; IR (KBr, cmꢀ1): 2972 (w), 2932 (w), 1753 (s), 1561 (s), 1488 (m), 1436 (m), 1308 (s),
1
1260 (s), 1129 (s), 1054 (s), 1015 (s), 979 (s), 825 (w), 805 (w), 761 (m), 729 (m); H
RMN (200 MHz, CDCl3): δ 7.54ꢀ7.51 (m, 1H), 6.78 (d, J= 4.4 Hz, 2H), 6.51ꢀ6.48 (m,
1H), 6.36ꢀ6.33 (m, 3H), 3.06 (q, J = 7.4 Hz, 4H), 1.34 (t, J= 7.6 Hz, 6H), 1.23 (s, 9H);
13C RMN (50 MHz, CDCl3): δ 163.1, 148.7, 134.7, 129.2, 125.7, 124.9, 119.5, 117.1,
111.1, 85.1, 27.3, 22.1, 13.0. HRMS FABS (M+H+) Calcd for C22H27BF2N3O2: 414.2164.
Found: 414.2169.
BODIPY 40.
According to GP1. 1b (50.0 mg, 0.170 mmol) and 4ꢀ
formylphenylboronic acid (76.0 mg, 0.510 mmol), Pd2(dba)3 (3.8 mg, 4.2x10ꢀ3 mmol),
TFP (2.9 mg, 0.013 mmol), and CuTC (96.9 mg, 0.510 mmol). The desired product (52.9
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