Negishi reaction in BODIPY dyes. Unprecedented alkylation by palladium-catalyzed C-C coupling in boron dipyrromethene derivatives

Article abstract of DOI:10.1039/c4ra00651h

Negishi reactions of 3-halogen and 3,5-dihalogen substituted BODIPYs with different organozinc reagents are reported as the first examples of this valuable palladium-catalyzed C-C coupling reaction into the family of the BODIPY dyes. It is demonstrated th

Full text of DOI:10.1039/c4ra00651h

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Negishi reaction in BODIPY dyes. Unprecedented
alkylation by palladium-catalyzed C–C coupling in
boron dipyrromethene derivatives†
Cite this: RSC Adv., 2014, 4, 19210
Gonzalo Duran-Sampedro,a Eduardo Palao,a Antonia R. Agarrabeitia,a
Received 22nd January 2014
Accepted 11th April 2014
a
b
a
*
Santiago de la Moya, Noel Boens and Marıa J. Ortiz
¨
´
DOI: 10.1039/c4ra00651h
www.rsc.org/advances
Negishi reactions of 3-halogen and 3,5-dihalogen substituted BODI- functionalization methodology is highly attractive for expand-
PYs with different organozinc reagents are reported as the first ing the diversity of the BODIPY family, especially for some
examples of this valuable palladium-catalyzed C–C coupling reaction typologies which are difficult to obtain directly by pre-functio-
into the family of the BODIPY dyes. It is demonstrated that the Negishi nalization.2e,6 However, functionalizing the BODIPY core is not
coupling is especially useful for obtaining interesting alkylated BODI- trivial, and in many cases critical problems arise concerning the
PYs, including synthetically-valuable asymmetrically-3,5-disubstituted control of the BODIPY reactivity (lack of reactivity, uncontrolled
BODIPYs.
reactivity, etc.).
Many of the most important BODIPY functionalization
reactions are based on the use of halogen-substituted BODIPYs.
Signicantly, 3-halo and 3,5-dihaloBODIPYs have been exten-
sively used, because they can be easily prepared by controlled
electrophilic aromatic substitution (SEAr) reactions in dipyrro-
methane precursors7 and, aerwards, submitted to nucleo-
philic substitution with alcohols, amines or enolates to give rise
to the corresponding substituted BODIPYs.3,7a–c,8 Moreover, 3-
halo and 3,5-dihaloBODIPYs have been also used as convenient
precursors of interesting carbon-substituted BODIPYs through
palladium-catalyzed C–C coupling reactions. Thus, Dehaen
et al. have reported the use of the Stille, Suzuki, Heck and
Sonogashira reactions for the preparation of valuable aryl,
alkenyl and alkynyl BODIPYs, with uorescence spanning the
visible spectrum, from a 3,5-dichloroBODIPY.9 On the other
hand, Ravikanth et al. have recently reported the preparation of
several symmetric and asymmetric BODIPY derivatives, with
interesting photophysical and electrochemical properties, by
Sonogashira and Suzuki reactions of the corresponding 3,5-
dihaloBODIPYs precursor.10
It should be noted that, to the best of our knowledge, only
aryl, alkenyl or alkynyl derivatives were obtained by applying the
above-mentioned palladium-catalyzed C–C couplings in BOD-
IPYs.1a–c,9ꢀ11 Strikingly, alkyl BODIPYs were not reported by
using those reactions, despite these derivatives are very inter-
esting dyes for many different technological applications (e.g.,
biological labelling and molecular probing), being mainly
prepared through to complex pre-functionalization routes
instead.12
BODIPY (boron dipyrrin or boron dipyrromethene) dyes
constitute one of the most important families of luminophores,
due to their easily tunable absorption and emission properties.1
These systems are highly interesting for the development of
valuable photonic applications, such as chemosensors and
probes, biological labels, laser dyes, potential photodynamic
therapy agents, and a plethora of photonic devices, including
solar light harvesting antennas or solar cells.2 Additionally,
chiral BODIPYs exhibiting some particular chiroptical proper-
ties (e.g., a clearly bisignated dichroic signal in the visible
region) have been recently highlighted as interesting dyes for
the development of useful technologies (e.g., CPL-based
sensing).3 There is, therefore, an understandable interest in the
synthesis of new BODIPY derivatives, not only for improving
useful photonic properties, but also for revealing the key
structural factors ruling them.
BODIPY dyes can be obtained by using two general meth-
odologies: (1) functionalization of pyrroles which are used as
precursors of the desired BODIPY aer nal boron complexa-
tion (pre-functionalization),1a,c,4 and (2) functionalization of the
BODIPY core (post-functionalization).1a–c,4b–d,5 The post-
aDepartment of Organic Chemistry I, Complutense University of Madrid, Ciudad
Universitaria s/n, 28040, Madrid, Spain. E-mail: mjortiz@ucm.es; Fax: +34 91 394
4103; Tel: +34 91 394 4309
bDepartment of Chemistry, Katholieke Universiteit Leuven, Celestijnenlaan 200f – bus
02404, 3001 Leuven, Belgium
† Electronic supplementary information (ESI) available: Experimental section,
Fig. S1, as well as 1H and 13C NMR spectra of new compounds. See DOI:
10.1039/c4ra00651h
On the other hand, Negishi reaction in BODIPYs is unprec-
edented, although it would allow the preparation of alkyl
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derivatives, as the Suzuki one would, but with the valuable the highest level of mono-coupling when 3,5-dibromoBODIPY 2
advantage of a high functional-group compatibility (including or 3,5-dichloroBODIPY 3 are used as starting halogenated
the labile BODIPY BF2 group), due to the nature of the Negishi- BODIPYs (see Experimental details in ESI†).
required organozinc reagents.13
Most of the Negishi alkylations tested took place satisfacto-
The above mentioned facts prompted us to essay the work- rily with high yields (Table 1, entries 1–10), demonstrating that
ability of the Negishi reaction in the BODIPY family, specially reaction control for mono-coupling of 3,5-dihaloBODIPY 2 and
directed to the synthesis of alkyl BODIPYs.
3 (entries 3, 5, 7 and 9) is possible. No signicant differences in
Herein we report the coupling reaction of 3-bromo, 3,5- reactivity were found between starting 3,5-dibrominated and
dibromo and 3,5-dichloroBODIPYs 1–3 with different organo- 3,5-dichlorinated BODIPYs (entries 2–5). For BODIPY iso-
zinc reagents ([R–Zn], Scheme 1), and demonstrate its versatility propylation (entry 10), the expected isopropyl to propyl isom-
for obtaining carbon-substituted BODIPYs, including alkylated erization was detected, which could be avoided by using an
and asymmetric derivatives.
appropriated, more sophisticated palladium catalyst (Pd-PEP-
HaloBODIPYs 1–3 (Scheme 1) were obtained straightfor- PSI-IPentCl).14 In contrast, benzylations took place with low
wardly by previously described pre-functionalization routes yields (entries 11 and 12), although conversion of starting 3,5-
based on SEAr reactions.7a–d Highly accessible [R–Zn] and dihaloBODIPY was almost complete. This can be accounted for
common Pd(PPh3)2Cl2 were used for the Negishi reactions by the high reactivity (methylene acidity) of the obtained ben-
tested. The results obtained are shown in Table 1.
zylated 5d and 4h. Nonetheless, this reactive property could be
Negishi reactions were conducted under standard reaction used in the future for the easy preparation of new BODIPY
conditions to reach the highest level of C–C coupling (normal derivatives, following the carbanion based BODIPY post-func-
conditions, N), or under controlled conditions (C, mainly by tionalization methodology described by Ziessel et al.5b It must
controlling the stoichioimetry and the reaction time) to reach be noted that, according to our knowledge, 5d and 4h are the
rst benzylated BODIPYs described up to date.
Arylations and alkynylations by Negishi reaction (entries 13–
17 in Table 1) were also conducted for the comparison with other
related palladium-catalyzed C–C coupling reactions. Thus, the
yields in the preparation of phenylated 5e and 4i by Negishi
reactions (entries 13 and 14) were only slightly higher than those
reported previously by Stille reactions by Dehaen et al.9 (56 vs.
50%, and 70 vs. 63%, respectively), but avoiding the use of the
more toxic organotin reagent required for the latter. On the other
hand, the yields in the preparation of phenylethynylBODIPYs 5f
and 4j by Negishi reactions (entries 15 and 16) were similar to
those obtained previously by Sonogashira reactions9 (54 vs. 57%,
and 56 vs. 59%, respectively). Finally, the yield in preparing (tri-
Scheme 1 Negishi reactions tested in BODIPYs.
methylsilyl)ethynylated 5g from 3 by Negishi reaction (entry 17)
was higher than that the reported by Ravikanth et al.,10 starting
from 2 and using the Sonogashira reaction (70 vs. 60%).
Table 1 Results for the Negishi reactions tested
An interesting application of the Negishi coupling is the
preparation of asymmetrically substituted 3,5-dialkylBODIPYs.
As an example, methylated chloroBODIPY 4d (entry 7 in Table 1)
was used as intermediate in the preparation of asymmetrically
dialkylated (5-methyl and 3-butyl) 5h (entry 18 in Table 1),
which was obtained with high overall yield (50%), from readily
available 3,5-dichloroBODIPY 3.
Finally, the study of the photophysical properties for the
novel alkylated BODIPYs was also conducted (Fig. 1 and S1 in
ESI†).
The narrow absorption and emission spectra of the dyes in
ethyl acetate (AcOEt) solution are in full accord with those of
classic BODIPY dyes,1,15 with absorption and emission maxima
around 500 and 520 nm, respectively. As found for common
diuoroboron dipyrrins, the Stokes shis are quite small.15 The
uorescence quantum yields (F) are lower than the measured
for commercial PM546, which is used as reference (Table 2). The
rather low F values can be accounted for by the enhanced
deactivation of the singlet excited state, due to the rotational
mobility of the p-tolyl group at the 8-position.16
Halo-
[Zn–R]
Major product
Yieldb
(%)
Entry BODIPY (reaction conditions)a (R/Y or R/R)
1
2
3
4
5
6
7
8
1
2
2
3
3
3
3
3
3
3
3
3
3
3
3
3
3
4d
ZnEt2 (N)
ZnEt2 (N)
ZnEt2 (C)
ZnEt2 (N)
ZnEt2 (C)
ZnMe2 (N)
ZnMe2 (C)
BuZnBr (N)
BuZnBr (C)
Zn(iPr)2 (C)
BnZnBr (N)
BnZnBr (C)
PhZnBr (N)
PhZnBr (C)
PhC^CZnBr (N)
PhC^CZnBr (C)
TMSC^CZnBr (N)
BuZnBr (N)
4a (Et/H)
5a (Et/Et)
4b (Et/Br)
5a (Et/Et)
64
86
61
73
75
80
77
52
62
70c
20
18
56
70
54
56
4c (Et/Cl)
5b (Me/Me)
4d (Me/Cl)
5c (Bu/Bu)
9
4e (Bu/Cl)
10
11
12
13
14
15
16
17
18
4f (iPr/Cl)/4g (Pr/Cl)c
5d (Bn/Bn)
4h (Bn/Cl)
5e (Ph/Ph)
4i (Ph/Cl)
5f (PhC^C/PhC^C)
4j (PhC^C/Cl)
5g (TMSC^C/TMSC^C) 70
5h (Me/Bu) 65
a
b
c
See reaction conditions in ESI. Isolated yield. 4f/4g
¼
2/1,
determined by 1H NMR (see ESI).
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BODIPY
labs(max) (nm)
lem(max) (nm)
Dn (cmꢀ1
)
F
PM546
4a
4b
4c
4d
4e
4h
5c
5d
494
500
509
505
505
506
509
509
514
506
504
516
528
522
519
523
523
525
524
521
400
620
707
645
534
642
526
599
371
569
0.85
0.02
0.07
0.14
0.11
0.12
0.17
0.12
0.13
0.13
5h
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In summary, we report the rst examples of the Negishi C–C
coupling reaction in BODIPYs (3-halo and 3,5-dihaloBODIPYs),
highlighting its workability for obtaining alkylated BODIPY
dyes, including synthetically-valuable asymmetrically-3,5-
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useful u-substituted alkyl BODIPYs for biomolecular probing).
Funding from the MINECO of Spain (MAT2010-20646-C04-
02) is gratefully acknowledged. G.D.-S. thanks the MICINN of
Spain for a predoctoral scholarship (FPI).
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