Straightforward synthesis of oligopyrroles through a regioselective S NAr reaction of pyrroles and halogenated boron dipyrrins

Article abstract of DOI:10.1021/ol500507f

A novel stepwise and regioselective nucleophilic aromatic substitution (S_NAr) reaction of halogenated boron dipyrrins (BODIPYs) with pyrroles has been developed under mild conditions with no catalyst needed and shown to be diversity oriented. The resultant pyrrole-substituted BODIPYs are interesting red and near-infrared (NIR) fluorescent dyes with absorption maxima up to 733 nm. Removal of the BF₂ protecting group of the 3-pyrrole or 3,5-dipyrrole-substituted BODIPYs provides a facial entry to oligopyrroles with direct 2,2′-bipyrrole linkages.

Full text of DOI:10.1021/ol500507f

Letter
pubs.acs.org/OrgLett
Straightforward Synthesis of Oligopyrroles through a Regioselective
SNAr Reaction of Pyrroles and Halogenated Boron Dipyrrins
Ting Jiang, Ping Zhang, Changjiang Yu, Jian Yin, Lijuan Jiao,* En Dai, Jun Wang, Yun Wei, Xiaolong Mu,
and Erhong Hao*
Laboratory of Functional Molecular Solids, Ministry of Education, Anhui Laboratory of Molecule-Based Materials, School of
Chemistry and Materials Science, Anhui Normal University, Wuhu, Anhui 241000, China
S
* Supporting Information
ABSTRACT: A novel stepwise and regioselective nucleophilic
aromatic substitution (SNAr) reaction of halogenated boron
dipyrrins (BODIPYs) with pyrroles has been developed under
mild conditions with no catalyst needed and shown to be
diversity oriented. The resultant pyrrole-substituted BODIPYs
are interesting red and near-infrared (NIR) fluorescent dyes
with absorption maxima up to 733 nm. Removal of the BF2
protecting group of the 3-pyrrole or 3,5-dipyrrole-substituted
BODIPYs provides a facial entry to oligopyrroles with direct
2,2′-bipyrrole linkages.
hort oligopyrroles,1 such as dipyrrins, pyrrolyldipyrrin,
especially unsymmetrical 2,2′-bipyrroles, are very difficult,
Stripyrrins, and tetrapyrroles, are versatile precursors for the although limited methods have been developed, including the
Paal−Knorr cyclization,4 the oxidative coupling of α-unsub-
synthesis of porphyrinoids and have also found wide
stituted pyrroles,5 Ullmann coupling,6 and other metal-
applications in medicinal chemistry, material science, and
mediated coupling reactions.7 It is thus highly desirable, and
supramolecular chemistry as anion-binding and cation-coordi-
nation reagents.1,2 Among those, tetrapyrroles featuring with
also of practical importance, to explore a new synthetic strategy
toward tetrapyrrole framework.
direct 2,2′-bipyrrole linkages are the core structure of many
contracted and expanded porphyrins.3−5 For example, they are
The α,ω-dihalogenated dipyrrins and their metal complexes,
as old porphyrin precursors, have recently been widely used for
key intermediates for the construction of isocorroles and
the metal-promoted construction of porphyrinoids.8−10 Broring
isoporphycenes by Vogel et al.3a,b Sessler et al. reported
oxidative dimerization of tetrapyrrole to [32]-
octaphyrin(1.0.0.0.1.0.0.0).3c There is a very limited number
of tetrapyrroles reported to date due to their lengthy total
synthesis.3 Reported tetrapyrroles were generally prepared with
limited diversity through condensations of bipyrroles and
triethyl orthoformate under acidic conditions3 (Figure 1).
However, construction of direct 2, 2′-bipyrrole linkages,
̈
et al. synthesized 10-heterocorroles from α,ω-dibrominated
dipyrrin with copper salt.8 Shinokubo et al. reported syntheses
of norcorrole, octaphyrin, azacorrole, and thioporphyrinoid
from a series of metal dihalogenated dipyrrins.9 The boron-
coordinated α,ω-dihalogenated dipyrrins (known as BODIPY)
with better stability than corresponding dipyrrin have shown
good reactivity toward various nucleophiles11a and also been
used to construct antiaromatic porphyrinoids by transition-
metal-mediated synthesis.11b On the other hand, BODIPYs12
are widely used as labeling dyes or fluorescence sensors in
biological systems due to their excellent photophysical
properties,13 and development of near-infrared (NIR) deriva-
tives of BODIPY has recently gained much attention.14 For
example, BF2 complexes of pyrrole-containing BODIPYs such
as BODIPY 576/589 and BODIPY 650/665 marketed by
Invitrogen and their analogues have been widely used as red
fluorescence dyes.15
Herein, we report a stepwise and regioselective aromatic
substitution reaction of halogenated BODIPYs with pyrroles.
The resultant pyrrole-substituted BODIPYs are interesting red
Figure 1. Existing method and our method for synthesis of
tetrapyrrole fragments.
Received: February 17, 2014
Published: March 26, 2014
© 2014 American Chemical Society
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Letter
and NIR fluorescent dyes and also provide a facial entry to a
series of novel tetrapyrroles through removal of BF2 protecting
group. The high efficiency in the preparation of pyrrole-
substituted BODIPYs is rather remarkable, with no catalyst
needed and being diversity oriented.
Scheme 2. Synthesis of Dyes 5a−c through SNAr Reactions
of Pyrroles
Initially, the reaction was performed by heating tetrachlori-
nated BODIPY 1a with neat pyrrole under argon (Scheme 1),
Scheme 1. Synthesis of Dyes 3 and 4 through SNAr Reaction
of Pyrroles
The pyrrole-substituted halogenated BODIPYs 3aa are
similarly well suited as starting materials for the synthesis of
unsymmetrical tetrapyrrole dyes which were not previously
obtainable. Reaction between 3aa and 2,4-dimethyl-3-ethyl-
pyrrole 2c smoothly gave unsymmetrical tetrapyrrole 6 in 58%
yield at 90 °C in toluene (Scheme 3).
Scheme 3. Synthesis of Dyes 6 and 7
Further removal of the BF2 protecting group using t-BuOK
in ethylene glycol18 successfully gave unsymmetrical tetrapyr-
role 7a cleanly. Similarly, tetrapyrroles 7b and 7c were also
easily obtained from the corresponding 4aa and 4ab in good
yields (Scheme 3). By contrast, the pyrrole-substituted
halogenated BODIPY 3aa under the same conditions gave
ethylene glycol substituted pyrrolyldipyrrin 7d in 58% yield.
The structures of 4aa, 6, and 7c have been confirmed by X-
ray crystallographic analysis (Figures 2 and 3). These dyes all
showed an almost planar structure for the dipyrrin core
(dihedral angles of two pyrrole rings in dipyyrin core are all less
than 12.2°; see the Supporting Information, Table S1). The
3,5-pyrrole substituents in 4aa and 6 lie slightly out of the plane
of the dipyrrin core, with deviations of 38.7°/38.6° and 24.7°/
from which a new reddish spot (later identified as 3aa) and a
new greenish spot (later identified as 4aa) were smoothly
generated and detected by TLC. By optimizing the reaction
temperature, we found that the reaction solely gave 3aa at 60
°C, while 4aa was selectively obtained at 120 °C with longer
reaction time. More interestingly, 1a showed higher reactivity
toward 2,4-dimethylpyrrole 2b. Simply mixing 1a and 2b in
toluene at 60 °C gave 4ab in 45% yield. Similar results were
obtained with 2,4-dimethyl-3-ethylpyrrole 2c. This SNAr
reaction reaction proceeded smoothly and gave similar results
in the presence of 5 equiv of triethylamine as an acid scavenger.
Subsequently, our synthetic strategy was extended to
halogenated BODIPYs 1b,c, from which the corresponding
dyes 4ba−ca were obtained in 32−47% isolated yields (Scheme
1). The presence of electron-withdrawing groups on the
halogenated BODIPYs enhances their reactivity toward
pyrroles as BODIPY 1a exhibits higher reactivity than 1b.
Our method also provides a novel route to dyes 4ca from
BODIPY 1c, which is a BF2-coordinated derivative of a pyrrole
antibiotic, a natural pigment possessing important biological
properties.1b,16
Next, meso-chlorinated BODIPY 1d17 also showed high
reactivity and was reacted with pyrroles 2a−c (Scheme 2) at
room temperature, giving meso-pyrrole-substituted BODIPYs
5a−c in 84−88% yields.
Figure 2. X-ray structure of 4aa: C, light gray; H, gray; N, blue; B, dark
yellow; F, bright green; Cl, green.
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Organic Letters
Letter
Figure 3. X-ray structures of 6 (a) and 7c (b): C, light gray; H, gray;
N, blue; B, dark yellow; F, bright green; Cl, green; Br, dark green.
58.9°, respectively. Intramolecular hydrogen bonds between the
hydrogen attached to the uncoordinated pyrrolic nitrogen and
the fluorine atoms in 4aa and 6 were observed. The observed
distances between N atoms of 3,5-substituted pyrroles and F
atoms were around 2.81−3.42 Å. Multiple intermolecular C−
H···F hydrogen bonds between F atoms and various hydrogen
atoms are formed due to the strong electron negativity of the F
atom. These strong intermolecular hydrogen bonds aid the
establishment of the crystal packing structure and make 4aa and
6 nearly parallel to each other in a slipped head-to-head
orientation (Figures S1 and S2, Supporting Information).
The molar absorption coefficients, the absorption and
emission maxima, fluorescence quantum yields, and Stokes
shifts of compounds 3−6 are summarized in Table S2
(Supporting Information). Their UV−vis absorption and
fluorescence spectra measured in hexane, dichloromethane,
and methanol are shown in Figures S3−S12 (Supporting
Information). Figure 4 shows the UV−vis absorption and
fluorescence spectra of 4ba, 4bb, and 4bc in CH2Cl2. In
comparison with parent BODIPY A (Table S2, Supporting
Information), significant spectral red-shifts (158 nm in
absorption, 162 nm in emission, respectively) were observed
for BODIPYs 4ba, indicating the enhancement in the π-
electron delocalization due to the existence of uncoordinated
pyrrole units. The gradual red-shift of the absorption and
emission has been observed with an increase of the alkyl
substituents on the uncoordinated pyrrole unit. 2,4-Dimethyl-3-
ethylpyrrole-substituted BODIPY 4bc absorbs/emits at 718/
760 nm in CH2Cl2, while 2,4-dimethylpyrrole-substituted
BODIPY 4bb and pyrrole-substituted BODIPY 4ba absorb/
emit at 700/739 and 658/689 nm, respectively. Adding halogen
atoms on the BODIPY core gives further spectral red-shifts as
BODIPYs 4aa, 4ab, and 4ac absorb/emit at 685/719, 708/760,
and 733/805 nm in CH2Cl2, respectively. 3-Pyrrole-substituted
BODIPY 3aa absorbs/emits at 617/648 nm in CH2Cl2, while
BODIPY 6 with addition of another 2,4-dimethyl-3-ethyl-
pyrrole absorbs/emits at 712/795 nm.
Figure 4. Normalized absorption (a) and fluorescence (b) spectra of
4ba, 4bb, and 4bc in CH2Cl2.
Figure 5. Absorption spectra changes of dyes 7c and 7d (1 × 10−5 M)
in CH2Cl2 after addition of TFA.
Tetrapyrroles 7a−c show broad absorptions around 600 nm.
The addition of TFA to the CH2Cl2 solution induced dramatic
absorption spectral red-shifts to above 700 nm (Figures S13−
16, Supporting Information). For example, absorption of 7c
red-shifts from 591 nm in CH2Cl2 to 771 nm after adding TFA
(Figure 5), while pyrrolyldipyrrin 7d red-shifts from 504 to 619
nm.
The fluorescence quantum yields of those dyes can be finely
tuned by the uncoordinated pyrroles at the 3/5-positions and
the polarity of solvents (Table S2, Supporting Information).
The fluorescence quantum yields were decreased from pyrrole
and 2,4-dimethylpyrrole to 2,4-dimethyl-3-ethylpyrrole when
installed at the 3/5-positions of the BODIPY core. Most of
those dyes show strong fluorescence in hexane (fluorescence
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quantum yields for 4ba, 4bb, and bc are 0.67, 0.37, and 0.31,
respectively) but give decreased fluorescence in methanol,
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halogenated BODIPYs with pyrroles without the usage of any
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ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental details, NMR, additional photophysical data, and
CIF. This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: jiao421@mail.ahnu.edu.cn.
*E-mail: haoehong@mail.ahnu.edu.cn.
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
This work is supported by the National Nature Science
Foundation of China (Grants Nos. 21072005, 21272007, and
21372011).
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