Synthetic Approach to Readily Accessible Benzofuran-Fused Borondipyrromethenes as Red-Emitting Laser Dyes

Article abstract of DOI:10.1021/acs.joc.8b02933

We took advantage of the chemoselective meso-functionalization of 2,3,5,6-tetrabromo-8-methylthioBODIPY 6 to prepare a series of 2,3,5,6-tetrabromo-8-arylBODIPY derivatives suitable for S_NAr substitution reactions with phenols exclusively at positions 3 and 5. Pd(0)-catalyzed intramolecular arylation reaction ensued on the remaining brominated positions 2 and 6 to give a new family of benzofuran-fused BODIPY dyes. This method utilizes readily available starting materials and allows for the preparation of the title compounds with excellent functional group tolerance. Moreover, it was demonstrated that the methodology described herein is amenable for the incorporation of biomolecules. The photophysical and lasing properties of the benzofuran-fused BODIPY dyes were thoroughly analyzed with the aid of electrochemical measurements and quantum mechanical simulations. These dyes show bright and intriguing emission (both fluorescence and laser) toward the red edge of the visible spectrum with remarkable tolerance under strong and continuous irradiation.

Full text of DOI:10.1021/acs.joc.8b02933

Subscriber access provided by TULANE UNIVERSITY
Article
Synthetic Approach to Readily Accessible Benzofuran-
Fused BODIPY as Red-Emitting Laser Dyes
José L. Belmonte-Vázquez, Edurne Avellanal-Zaballa, Ernesto Enríquez-Palacios, Luis Cerdán, Ixone
Esnal, Jorge Bañuelos, Clarisa Villegas-Gómez, Iñigo Lopez Arbeloa, and Eduardo Peña-Cabrera
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02933 • Publication Date (Web): 31 Jan 2019
Downloaded from http://pubs.acs.org on February 1, 2019
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a service to the research community to expedite the dissemination
of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in
full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully
peer reviewed, but should not be considered the official version of record. They are citable by the
Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore,
the “Just Accepted” Web site may not include all articles that will be published in the journal. After
a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web
site and published as an ASAP article. Note that technical editing may introduce minor changes
to the manuscript text and/or graphics which could affect content, and all legal disclaimers and
ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or
consequences arising from the use of information contained in these “Just Accepted” manuscripts.
is published by the American Chemical Society. 1155 Sixteenth Street N.W.,
Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 63
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Synthetic Approach to Readily Accessible Benzofuran-
Fused BODIPY as Red-Emitting Laser Dyes
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
†
≠
†
José L. Belmonte-Vázquez, Edurne Avellanal-Zaballa, Ernesto Enríquez-Palacios, Luis
¥
¥
≠
≠ ,*
†
Cerdán, , Ixone Esnal, Jorge Bañuelos, Clarisa Villegas-Gómez, Iñigo López
Arbeloa, Eduardo Peña-Cabrera
≠
†,*
†
Departamento de Química. Universidad de Guanajuato, Noria Alta S/N. Guanajuato, Gto.
Mexico 36050
≠
Departamento de Química Física. Universidad del País Vasco-EHU, Apartado 644,
48080, Bilbao, Spain.
¥
Instituto de Química-Física “Rocasolano”, CSIC. Serrano 119, 28006 Madrid, Spain
Email: jorge.banuelos@ehu.eus, eduardop@ugto.mx
Abstract
We took advantage of the chemoselective meso-functionalization 2,3,5,6-tetrabromo-8-
methylthioBODIPY 6 to prepare a series of 2,3,5,6-tetrabromo-8-arylBODIPY derivatives
suitable for S Ar substitution reactions with phenols exclusively at the 3-and 5-positions.
N
Pd(0)-catalyzed intramolecular arylation reaction ensued on the remaining brominated 2- and
6
-positions to give a new family of benzofuran-fused BODIPY dyes. This method utilizes
readily available starting materials and allows for the preparation of the title compounds with
excellent functional group tolerance. Moreover, it was demonstrated that the methodology
described herein is amenable for the incorporation of biomolecules. The photophysical and
lasing properties of the benzofuran-fused BODIPY dyes were thoroughly analyzed with the
aid of electrochemical measurements and quantum mechanical simulations. These dyes show
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 63
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
bright and intriguing emission (both fluorescence and laser) towards the red edge of the
visible spectrum with remarkable tolerance under a strong and continuous irradiation.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Introduction
1
Borondipyrromethenes (BODIPYs) 1 (Figure 1), are arguably some of the most versatile
2
3
fluorophores there are. Plenty has been written about their synthesis, post-functionalization,
4
5
6
water solubility, halogenated derivatives. Similarly, there is vast information regarding
7
their applications: in organic photovoltaic devices, as components of novel light active
8
9
10
materials, as fluorescent tools, as sensitizers for dye-sensitized solar cells, as sensors for
1
1
12
reactive oxygen species, and in photodynamic therapy, just to mention a few topics.
There are well-established fluorophores with a marked diversity of structures that emit at
1
3
specific wavelengths. However, the BODIPYs core structure is one of the few capable to
fluoresce over the whole visible and near infrared (NIR) regions of the electromagnetic
spectrum, if properly functionalized (Figure 1).2,14
ACS Paragon Plus Environment

Page 3 of 63
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Figure 1. Panchromatic properties of BODIPY dyes.
The possibility to induce a bathochromic shift on the optical properties of these dyes is highly
desirable. Many imaginative attempts have been tested to design red-emitting BODIPYs.15
The reason of such search relies on the serious drawbacks of most of the available
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
6
fluorophores in that spectral region for their optimal practical application. As a matter of
fact, cyanine dyes are able to provide spectral bands deep in the red edge, even reaching the
NIR, but with low fluorescence efficiencies owing to their push-pull and conformationally
1
7
flexible chromophores. On the other hand, oxazine dyes render bright emission but are
1
8
easily photobleached. One way to circumvent such limitations is by shifting the spectral
2
bands of BODIPYs, characterized by their excellent photophysics and robustness, to the red
4
edge thanks to the chemical versatility of its dipyrrin core. These red-emitting BODIPYs are
used as building blocks to prepare polymers that can be used in photovoltaics, solar-cells,
photodetectors, etc.19 Such compounds find numerous applications in bio-medicine and
related areas. Thus, NIR-emitting BODIPYs have been used as pH probes and in bio-
2
0
21
imaging, in photodynamic therapy, and as molecular probes for reactive oxygen species
ROS).22
(
A well-known approach to red-shift both absorption and emission of BODIPY dyes is to
reduce their HOMO-LUMO gap by extending their conjugated system. Thus, the groups of
Wu, 23 Rurack, Jiao, Okujima, Ziessel Shinokubo, Kubo, among others, have
24
25
26
27
28
29
reported a variety of different BODIPY structures featuring extended conjugated systems
(Figure 2). Moreover, Wu and Ni have published a review with additional conjugated
BODIPY structures.30
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 63
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
OMes
OMes
R
B
Ph
Ph
R
R
Ph
R
Ph
N
N
F
N
N
F
N
N
F
N
N
F
B
B
B
F
F
R
F
R
X
F
R
Wu
Ono, Rurack
Jiao
Okujima
Ar
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
N-R
Ar
B
RO
OR
Br
Br
N
N
N
N
N
N
S
B
S
B
F
F
F
F
O
O
N
F
N
S
S
B
Ar
F
Ar
R
R
Kubo
Wu
Ziessel
Shinokubo
Figure 2. Representative examples of BODIPYs with extended conjugation.
The so-called Keio Fluors 2, are BODIPY dyes with extension of the conjugation including
heterocycles, specifically, furan. These feature results in dyes with improved properties, such
as color tunability, sharp spectral bands, high extinction coefficients and fluorescence
quantum yields. Additionally, they show little dependence of their brightness with solvent
polarity. A significant disadvantage is that each derivative must be prepared by a linear
synthesis comprising seven steps, leaving little or no room for further modifications of the
final products (Scheme 1).31
seven steps
O
O
N
N
F
B
F
Br
CHO
O
R
R
Keio Fluors 2
Scheme 1. Linear synthesis of Keio Fluors
The synthesis of a single regioisomer 3 was described in 2010, using an alternative
methodology (Scheme 2).32
ACS Paragon Plus Environment

Page 5 of 63
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
R
B
R
R
B
4
linear steps
stepwise
Br
Br
N
N
F
N
N
F
N
N
F
N
B
F
cat. Pd(0)
H
O
O
Cl
F
Cl
O
O
F
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
R= Me
Scheme 2. Synthesis of BODIPY 3
After analyzing the synthetic sequence, one realizes that it becomes quite an undertaking to
prepare different analogues for each of them would require repeating the whole process to
vary the meso-substituent. Moreover, the introduction of additional functional groups on the
benzofuran system would need a substituted o-bromophenol.
Herein we disclose a fully flexible method that allows the preparation of a novel family of
benzofuran-fused BODIPY dyes. Easy modifications in the synthesis permits variations both
at the meso-position and the benzofuran substitution pattern since the latter only requires
substituted phenols. This method also features the use of an advanced, commercially
available BODIPY starting material 4, a complete chemoselective control over three reaction
sites, and the preparation of BODIPY dyes with unique architectures and important
33
photophysical and laser properties. In 2016, we reported the synthesis of multifunctional
BODIPY 5 and demonstrated that it displayed orthogonal reactivity, i.e., the C-S bond was
3
4
activated under the Liebeskind-Srogl cross-coupling reaction (LSCC) conditions, leaving
the C-Br bond intact. This chemoselectivity allowed us to introduce a variety of functional
groups in a programmed fashion on the periphery of the BODIPY core. Now we decided
challenge even further the chemoselectivity of novel BODIPY building block 6 and apply it
this time to the preparation of a new family of benzofuran-fused BODIPY dyes (Figure 3).
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 63
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Previous work:
LSCC and S Ar-like
reactions
N
SMe
Suzuki, Stille, Sonogashira
Suzuki, Stille, Sonogashira
Br
Br
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
N
N
B
F
F
Knoevenagel reaction
Knoevenagel reaction
5
This work:
LSCC reaction
SMe
Pd-catalyzed arylations
SNAr-inactive
Pd-catalyzed arylations
SNAr-inactive
Br
Br
N
N
B
Br
F Br
F
Activated f or S Ar reactions
and f or Pd-catalyzed cross-
coupling reactions
Activated f or S Ar reactions
N
N
6
and f or Pd-catalyzed cross-
coupling reactions
Figure 3. BODIPY dyes with orthogonal reactivity.
This type of benzofuran-fused BODIPYs readily available by this novel approach, display
well red-shifted absorption and emission bands. Hereafter, we describe the photophysical and
lasing properties of the benzofuran-fused BODIPYs and demonstrate their viability as laser
dyes endowed with high laser and fluorescence efficiencies, and high photostability under
strong and prolonged pumping. To the best of our knowledge, the laser capabilities of the
red-emitting benzo-fused BODIPYs overall are almost hitherto unexploited (just early
conference proceedings from SPIE).35
ACS Paragon Plus Environment

Page 7 of 63
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Results and Discussion
Retrosynthetic analysis. The retrosynthetic analysis is shown in Scheme 3. The final
products 9 will be formed after a Pd-catalyzed arylation reaction of 8.36 Bis-phenoxy-
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
containing intermediate 8 would be formed after a double S Ar of 7 with substituted phenols
N
under basic conditions, at exclusively at the 3- and 5-positions since only those C-Br bonds
3
7
are activated towards the addition-elimination process. Meso-aryl substituted BODIPY 7
would be prepared from the chemoselective LSCC under neutral conditions leaving intact
33
the four brominated positions. This selectivity would allow for the introduction of varied
aryl groups at the meso-position, a key step of our synthetic plan. Finally, tetrabrominated
intermediate 6 would be produced from commercially available 4.
Chemoselective
LSCC reaction
Pd-catalyzed
arylation
Ar
B
Pd-catalyzed
arylation
Ar
B
Ar
B
7
1
Br
Br
Br
Br
Br
N
N
N
N
6
N
N
2
R
R
5
3
O
F
O
O
F
O
Br
F
Br
F
R
F
R
F
9
8
7
SNAr
SNAr
SMe
SMe
Br
N
N
F
N
N
B
B
F
Br
F
Br
F
4
6
Commercially available
Facile tetrabromination
Scheme 3. Retrosynthetic analysis to prepare benzofuran-fused BODIPY dyes
Synthesis. Tetrabromination of commercially available 8-methylthioBODIPY 4 was carried
out according to eq 1.
SMe
SMe
5
equiv NBS
(1)
Br
Br
N
N
B
N
N
B
AcOH, rt, 12 h
F
Br
F Br
F
F
4
6
, 50%
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 63
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Next, the key step of our synthetic plan followed, i.e., the chemoselective LSCC on 6 in the
presence of other reactive sites (Table 1).
Table 1. Optimization of the LSCC reaction on 6.a
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
SMe
Pd(0) cat, TFP
Br
Br
+
Br
Br
N
N
F
N
N
Cu(I) additive, THF, 55 C, 2 h
B
B
Br
F
Br
Br
F F Br
B(OH)2
TFP=
P
6
10
O
3
Entry
Equiv boronic
Cu source
CuTCc
Pd source
% of
conversion
72
b
acid
1
1
2
3
4
5
6
Pd (dba)
2
3
3
3
3
3
3
3
3
3
3
CuTC
Pd (dba)
80
24
2
CuMeSald
Pd (dba)
2
e
CuO PPh
Pd (dba)
65
2
2
2
-f
CuI
Pd (dba)
2
CuTC
Pd(PPh3)4g
10
a
Conditions: 6 (1 equiv), Pd(0) (2.5 mol%), TFP (2.5 mol%), Cu(I) source (equimolar with
b
c
respect to the boronic acid). Determined by HPLC. Copper(I) thiophene-2-carboxylate.
d
e
f
Copper(I) 3-methylsalicylate. Copper(I) diphenylphosphinate. No product was formed.
No TFP was used.
g
The typical Cu(I) sources for the LSCC reaction were tested. All of them, except CuI yielded
the desired product (entry 5), however, the best results were observed with CuTC (entry 1).
A further increase in the yield was observed when 3 equiv of the boronic acid were used
(entry 2). Notably, under these reaction conditions, only BODIPY 10 was produced along
with trace amounts of other colored compounds in quantities too small to be characterized.
ACS Paragon Plus Environment

Page 9 of 63
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
This key result allowed the selective functionalization of the meso-position leaving the other
brominated positions available to be manipulated at will.
Once the best conditions were determined, we set out to react 6 with several arylboronic acids
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(Table 2) to study the scope of the LSCC reaction.
Table 2. LSCC reaction on BODIPY 6.a
SMe
Ar
B
Pd (dba) , TFP
2
3
Br
Br + 3 Ar-B(OH)2
Br
Br
N
N
F
N
N
3 CuTC, THF, 55 °C
B
Br
F
Br
Br
F
Br
F
6
10-15
% Yieldb
Entry
Ar-
Reaction time
Compound
10
1
2 h
50
2
1 h
76
11
OHC
3
4
5
6
1 h
40 min
2h
38
63
18
83
12
13
14
15
MeO
N
1 h
a
Conditions: 6 (1 equiv), boronic acid (3 equiv), Pd (dba) (2.5 mol%), TFP (2.5%), CuTC
3 equiv), in THF at 55 °C. Isolated yield.
2
3
b
(
The LSCC took place smoothly in the set of phenols that we studied to give the meso-aryl-
substituted products in modest to good yields in relatively short reaction times. Electron-rich
boronic acids gave the highest yields (entries 4 and 6). No detrimental effect due to sterics
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 63
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
was observed when o-tolylboronic acid was employed (entry 2). Once derivatives 10-15 were
obtained, the nucleophilic substitution of phenol at the 3-position was explored. The results
are given in Table 3.
Table 3. Nucleophilic substitution of phenol on derivatives 10-15.a
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Ar
OH
Ar
B
6
equiv Na CO
2 3
Br
Br + 6
Br
Br
N
N
N
N
B
F
CH CN, 110 °C
3
Br
F Br
O
F O
F
10-15
16-20
Entry
Ar
Reaction time (h)
% Yieldb
Compound
16
1
6
80
2
3
4
5
6
3
3
5
3
-
77
57
72
60
-c
17
18
19
20
21
OHC
MeO
N
a
Conditions: BODIPYs (1 equiv), phenol (6 equiv), Na CO (6 equiv), sealed tube.
Isolated yields. Decomposition of the BODIPY was observed.
2
3
b
c
3
2
Phenol was added to BODIPYs 10-15 under basic conditions in acetonitrile at 110 °C. The
two-fold substitution reaction took place uneventfully to give 3,5-diphenoxy-subtituted
BODIPY dyes in good yields (entries 1-5). However, when trying to add phenol to BODIPY
1
5, decomposition of this compound was observed.
Next, the polyfunctionalized BODIPY so prepared were subjected to the Pd-catalyzed
intramolecular arylation (Chart 1).
ACS Paragon Plus Environment

Page 11 of 63
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Chart 1. Pd-catalyzed arylation of BODIPYs 16-20.a,b
Ar
Ar
B
Pd(OAc) , PPh
3
Br
Br
2
N
N
F
N
N
B
K CO , toluene, 150 °C
2 3
O
F F
O
O
F
O
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
6-20
22-26
CHO
N
N
B
N
N
F
N
N
F
B
B
F
O
F
O
O
O
O
O
F
F
22, 7 h, 59%a
23, 6 h, 66%
24, 5 h, 67%
OMe
N
N
B
N
N
F
B
O
F
O
O
O
F
F
2
5, 6 h, 48%
26, 6 h, 72%
a
Conditions: BODIPY (1 equiv), Pd(OAc) (0.05 equiv), PPh (0.1 equiv), K CO (3 equiv),
2
3
2
3
b
in toluene at 150 °C in a sealed tube. Isolated yield.
3
8
In sharp contrast to the reaction conditions that gave rise to isomer 3, two-fold arylation
reaction of dyes 16-20 was achieved under mild conditions to furnish the cyclized products
in yields that ranged from 48% to 72%. The electronic properties of the meso-aryl ring did
not seem to have any significant influence in either the reaction time, or the resulting isolated
yield.
We then decided to study the scope and limitations of the overall process using various
substituted phenols (Table 4). Compound 11 was chosen to start the sequence because it has
hindered rotation around the Cmeso-aryl bond. This feature increases the probability of
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 63
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
observing a high fluorescent quantum yield ( ) in the final products due to restricted
fl
rotation of said bond, thereby inhibiting non-radiative relaxation pathways.39
Table 4. Addition-elimination reaction of substituted phenols on tetrabromoBODIPY
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1.a
1
OH
Na CO
2
3
Br
Br +
Br
Br
N
N
F
N
N
B
CH CN, 110 °C
B
3
R
Br
Br
O
F O
F
F
1
1
27-31
R
R
% Yieldb
Entry
Phenol derivative
OH
Reaction time
Compound
27
1
2 h
2 h
1 h
79
F
2
3
90
90
28
29
n-hexyl-O
OH
OH
OH
4
5
1 h
2h
81
58
30
31
I
OH
O
B
O
OH
OH
-c
-d
6
7
2.5 h
32
33
15 min
a
Conditions: BODIPY (1 equiv), phenol (6 equiv), Na CO (6 equiv), in MeCN at 110 °C
2
3
b
c
in a sealed tube. Isolated yields. The product decomposed on chromatography (SiO -gel)
purification. Decomposition was observed.
2
d
Addition of substituted phenols took place as expected. All the products were obtained,
except when 4-hydrophenylpinacol boronate, and 1-hydroxypyrene were used, for
decomposition was observed in both cases (entries 6 and 7). Addition of the rest of the
ACS Paragon Plus Environment

Page 13 of 63
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
substituted phenols and naphthol was carried out under mild reaction conditions and short
reaction times (1-2 h) to yield the highly colored products in good to excellent yields (entries
1-5).
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
With derivatives 27-31 in hand, we proceeded to study their Pd(0)-catalyzed ring-closure to
yield the corresponding benzofuran-fused products. The results are illustrated in Chart 2.
Chart 2. Pd-catalyzed arylation of BODIPYs 27-31.a,b
Br
Br
N
N
F
B
Pd(OAc) , PPh3
2
O
F
O
N
N
F
B
K CO , toluene, 150 °C
O
O
2
3
F
R
R
R
R
27-31
34-37
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 63
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
F
F
n-hexyl-O
O-n-hexyl
N
N
F
N
N
F
B
B
O
O
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
F
O
O
F
3
4, 6 h, 75%
35, 7 h, 69%
N
N
F
N
N
F
B
B
F
O
O
O
O
F
3
6, 6 h, 64%
37, 7 h, 36%
I
I
N
N
F
B
O
O
F
38, 30 min, -
a
Conditions: BODIPY (1 equiv), Pd(OAc) (0.05 equiv), PPh (0.1 equiv), K CO (3 equiv),
in toluene at 150 °C in a sealed tube. Isolated yields.
2
3
2
3
b
Satisfyingly, the cyclization reaction took place to produce the final products in moderate to
good yields. Iodine-containing derivative 38 was not formed since quick decomposition of
the starting material was observed within the first 30 min. Presumably, the more reactive
iodide participated in undesired reaction in the presence of Pd.
Incorporation of two biomolecules. To demonstrate the applicability of the methodology
described herein, two phenolic biomolecules were chosen to be incorporated to the BODIPY
core: estrone and N-BOC-L-tyrosine methyl ester. TetrabromoBODIPY 13 was chosen as the
starting material since the o-tolyl analogue 11 would give rise to diastereoisomeric final
ACS Paragon Plus Environment

Page 15 of 63
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
products due to its hindered rotation around the meso-sigma bond. To this end, both
biomolecules were reacted with 13 under the reaction conditions shown in Tables 3 and 4
(Scheme 4) yielding the expected products in good yields and short reaction times.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
OMe
O
Na CO
2
3
OMe
NHBoc
Br
Br
1
3 +
N
N
F
NHBoc
B
BocHN
CH CN, 110 °C
3
MeO
OMe
HO
O
F
O
O
O
39, 1 h, 71%
MeO
O
Br
Br
N
N
Na CO
H
2
3
B
O
O
F F
1
3 +
H
H
H
O
CH CN, 110 °C
3
H
O
H
HO
H
H
H
40, 1 h, 70%
Scheme 4. Reaction of estrone and N-BOC-L-tyrosine methyl ester with BODIPY 13.
We then proceeded to carry out the arylation reaction on both 39 and 40 that would produce
the final products according to the conditions depicted in Charts 1 and 2. Cyclization of 39
gave the fused derivative 41 in 68% yield after 6 h (eq 2).
OMe
MeO
O
OMe
O
NHBoc
BocHN
Pd(OAc) , PPh3
2
(2)
3
9
K CO , toluene, 150 °C
N
N
2
3
B
O
O
F F
41, 6 h, 68%
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 63
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Cyclization of 40 posed an interesting regiochemistry issue since the estrone fragment has
two nonequivalent reaction sites (Figure 4).
H
Br
O
N
O
B
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
H
H
O
F F
H
N
H
B
O
N
H
B
O
F F
H
H
O
F F
H
42
40
43
Figure 4. The two possible regioisomers that could be produced from the cyclization
reaction of 40.
Bearing these aspects in mind, the Pd-catalyzed arylation reaction on BODIPY 40 was
carried out (eq 3). Even though the overall isolated yield was low (34%), only regioisomer
4
2 was obtained after 6 h.
MeO
O
O
Pd(OAc) , PPh3
H
2
H
4
0
(3)
N
N
K CO , toluene, 150 °C
B
H
H
2
3
H
H
O
O
F F
2, 34%, 6 h
4
Inspection of the NMR data led us to this conclusion. If isomer 43 had been formed, in
addition to the characteristic AA´XX´coupling pattern of the 8-(p-MeOphenyl) fragment, and
a singlet of the pyrrole moiety, two doublets should appear in the aromatic region due to the
cis-hydrogens from the estrone fragment (red protons in Figure 5). On the other hand, if 42
was formed, the two aromatic protons of estrone would be para- to each other (blue protons
in Figure 5), and therefore uncoupled. Indeed, the latter is the pattern we observe.
ACS Paragon Plus Environment

Page 17 of 63
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
singlet
singlet
singlet
H
H
O
O
H
H
H
H
H
H
N
N
B
F F
B
F F
H
H
doublet
O
O
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
H doublet
H
singlet
NOE
4
3
4
2
1
Figure 5. Expected H NMR signals of isomers 42 and 43.
The actual COSY spectrum of 42 is illustrated in Figure 6, showing no cross-peaks between
aromatic protons d and e.
Figure 6. Aromatic region of the COSY spectrum of estrone-fused BODIPY 42.
X-ray structure of 25. BODIPY 25 was crystallized by diffusion from petroleum
ether/CH Cl (Figure 7). The heterocyclic fragment of 25 is almost planar, displaying a very
2
2
slight concavity at the center. On the other hand, the B atom has a tetrahedral geometry (the
F-B-F angle is 110°, and the N-B-N angle is 104°) and lies off the plane by 10°. The 8-aryl
ring is in a 55° angle with respect to the BODIPY plane owing to the steric hindrance between
the hydrogens placed at ortho position of the ring and those at the chromophoric positions 1
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 63
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
and 7. The X-ray structure of the tolyl analogue 22, was already reported and displays very
similar features.32
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Figure 7. X-ray structure of 25 (ORTEP drawing, 50% probability). The corresponding
crystallographic date are listed in Table S3.
Photophysical properties
The fusion of benzofuran rings to the - positions of the dipyrrin core extends the π-system
and, in turn, entails a pronounced bathochromic spectral shift that pushes the spectral band
towards the red spectral window (Figure 8 and S1-S3). In contrast, the meso-aryl group has
no effect in the spectral band positions. In fact, in the compounds bearing methyl at ortho
position of the 8-phenyl, the sterical hindrance places this ring almost orthogonal to the
dipyrrin plane (dye 23). But even in absence of such alkylation (dye 22 or 26 for example in
Chart 1) the 8-phenyl is also twisted (around 60º) , owing to steric hindrance with the
hydrogens at chromophoric positions 1 and 7, and, hence, it is not electronically coupled to
the chromophoric core, Such red shift is strengthened by the addition of larger and more
conjugated aryls groups to the chromophoric core. For instance, in dye 37, with an aromatic
ACS Paragon Plus Environment

Page 19 of 63
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
framework comprising up to seven aromatic rings, the spectral bands are located well above
6
00 nm (Figure 8). The electrochemistry measurements reveal that all the dyes have a similar
cyclic voltammogram featuring two well-resolved and reversible anodic (around 1.25 V) and
cathodic (around -0.75 V) waves (Figure 9 and S4). The extension of the chromophoric
framework (dye 37) implies a reduction of both redox potential (with regard to its analog 23,
Figure 9), in agreement with the calculated lower energy gap between the frontier molecular
orbitals (from 5.80 eV in 23 to 5.73 eV in 37) and the recorded bathochromic shift (Figure
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
8
).
Figure 8. Absorption, normalized fluorescence, and laser (dual emission depending on the
dye concentration) spectra of dye 23 and its analogue 37, with additional fused phenyl rings,
in ethyl acetate. The spectra of the rest of compounds are included in Figure S1-S3.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 63
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Figure 9. Cyclic voltammograms and calculated contour maps and energies of the frontier
orbitals for compounds 23 and 37. Additional voltammograms of representative compounds
are collected in Figure S4.
Despite the number of rings fused to the dipyrrin core, and the ensuing structural stress, the
whole chromophore remains planar (for instance, deviations lower than 2º in compound 26,
even in the excited state). As a result of this planar and rigid molecular structure, reflected in
-1
a low Stokes shift (overall lower than 500 cm , Table S1), the aromaticity is high (as testified
by Bonds Length Alternation, BLA, parameter around 0.02 in both ground and excited state).
These features explain the remarkable high absorption probability (reaching values higher
ACS Paragon Plus Environment

Page 21 of 63
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
5
-1
-1
8
-1
than 2·10 M cm , Table 5), notable radiative rate constant (k > 2·10 s , Table 5) and
fl
low internal conversion probability (Table 5). Therefore, these conformationally restricted
and symmetrical red-emitting dyes display a bright fluorescence response, approaching a
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
8
00% in apolar media (Table 5). It should be highlighted that the presence of unconstrained
-aryl fragments with conformational freedom, efficiently quenches the fluorescence
4
0
response in simpler and more compact BODIPYs. In contrast, in the herein tested dyes, the
extension of the -system through the aryls fused to the pyrroles, shifts the electronic density
away from the key meso position, avoiding, or at least hampering, the quenching pathway
3
3
associated to the 8-aryl motion. In fact, those dyes sharing the same chromophoric unit
(dipyrrin fused with benzofurans), but differing in the meso-substitution, show similar and
high fluorescence quantum yields (Table 5) regardless of the conformational mobility of the
8
-aryl (unconstrained, twisting angle of the phenyl around 65º in dyes 22 and 26, or
constrained, orthogonal ortho-tolyl in 23) or its functionalization (electron donor para-
methoxy in 25). The only exception to the rule is 24 with a para-formylated 8-aryl, which
shows an unexpected low fluorescence response (Table 5). Such exemption will be
rationalized below.
Table 5. Photophysical properties of red-emitting benzofuran-fused BODIPYs in
cyclohexane. The whole photophysical data in more solvents are listed in Table S1.
λab

max
-1
λfl
(nm)
St
τ
(ns)
k
fl
8 -1
k
nr
8 -1
4
-1
-1
(nm) (10 M ·cm )
(cm )
345
260
540
290
330
250
ϕ
(10 s ) (10 s )
22
548.5
586.5
592.5
583.5
586.0
581.5
21.5
21.5
13.7
20.0
15.6
17.3
596.5
595.5
612.0
593.5
597.5
590.0
0.88
0.88
0.63
0.88
0.84
0.95
4.09
4.21
2.47
4.10
3.99
4.02
2.15
2.09
2.55
2.14
2.10
2.35
0.29
0.29
1.49
0.29
0.40
0.14
2
3
24
2
2
3
5
6
4
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 22 of 63
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
3
3
3
4
5
6
7
1
592.0
591.5
613.0
586.5
596.5
19.0
23.2
12.9
18.0
17.9
603.0
602.0
625.0
596.5
611.5
310
295
315
285
410
0.96
0.89
0.81
0.81
0.88
4.12
4.11
4.31
3.94
4.04
2.33
2.16
1.89
2.07
2.18
0.09
0.27
0.43
0.47
0.30
42a
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
a42 was insoluble in cyclohexane, thus, the reported data were recorded in diethylether
The evolution of the fluorescence efficiency with the solvent depends both on the type of
functional groups decorating the chromophoric backbone, and on the number of fused rings
(Figure 10 and Table S1). Thus, the presence of heteroatoms, like fluorine 34, or alkyl groups
(
bulky tert-butyl in 36) or a functionalized aliphatic chain (tyrosine biomolecule in 41) in the
fused benzofuran, renders highly fluorescent dyes in all the considered solvents. In contrast,
the addition of alkoxy chains (35) induces a progressive decrease of both the fluorescence
efficiency and the fluorescence lifetime with the solvent polarity (down to 29% and 1.67 ns,
respectively, in methanol, Table S1). Such tendency is consistent with the activation of an
intramolecular charge transfer (ICT) state in polar media. Thus, the benzofuran itself could
act as an electron donor owing to its oxygen heteroatom at the -pyrrolic position. The
additional presence of alkoxy groups in the periphery increases such electron donor character,
thereby being high enough as to switch on the non-fluorescence ICT. Indeed, in the contour
maps depicted in Figure 9, it can be visualized some electron transfer from the benzofuran to
the dipyrrin upon excitation (from HOMO to LUMO). Likely, such charge separation is
enlarged with fused benzofuran bearing alkoxy moieties, further favoring the non-radiative
energy loss through the claimed ICT. Moreover, similar red-emitting dyes have been reported
41
in the literature but with nitrogen instead of oxygen (fusion of indole). The higher electron
donor ability of the aza group induced a more pronounced spectral red shift but lower
fluorescence efficiencies than the herein tested analog 26, likely related to a higher charge
ACS Paragon Plus Environment

Page 23 of 63
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
transfer probability. In this line of reasoning, the presence of electron withdrawing groups at
the 8-aryl moiety, albeit moderately weak like the formyl group in dye 24, could reinforce
the formation of ICT processes, owing to the induced push-pull character (from the alkoxy-
containing benzofuran to the formylated 8-phenyl group), explaining the above-mentioned
unexpected quenching of this dye in polar media (Figure 10 and Table 5). To unambiguously
back up the ongoing ICT as the key process which rules the fluorescence response in these
last dyes (24 and 35), we have measured the photophysical properties of the structurally
related analogs 22 (bearing a non-formylated 8-phenyl ring) and 24 (with the said formylated
ring) in a battery of solvents with different physicochemical properties (Table S2). Whereas
in the former dye 22 the fluorescence quantum yield remains high (always higher than 0.84,
Table S2 and Figure S5) regardless of the solvent properties (described by the normalized
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
4
2
E (30) solvent scale ), in the last dye 24 not only the fluorescence quantum yields are lower,
T
but also the values show a marked dependency on the solvent polarity (from 0.63 in
cyclohexane down to 0.37 in acetonitrile, Table S2 and Figure S5). Such decrease of the
fluorescence efficiency with the solvent polarity is a fingerprint of an ongoing dark ICT,
which quenches the emission from the locally excited (LE) state, mainly in polar media where
the low-lying ICT is further stabilized. Indeed, the recorded fluorescence quantum yield for
dye 24 in a polar/protic solvent (methanol) does not follow the expected trend (Figure S5)
and the value is higher (0.44, Table S2). Such exception is likely due to a specific interaction
with the electron donor (oxygen atom of the benzofuran) which hampers the population of
the photoinduced ICT state.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 24 of 63
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Figure 10. Evolution of the fluorescence quantum yield of the herein reported novel red-
emitting BODIPYs with the tested media (from apolar cyclohexane in grey to polar methanol
in blue).
On the other hand, compounds 37 and 42, bearing the highest number of fused aryl fragments,
show low fluorescence efficiencies in polar media (down to 50% in methanol, Figure 10),
albeit the fluorescence lifetimes remain similar (around 3 ns) (Table 5). In these highly
extended derivatives, the structural stress to keep the whole chromophore planar should be
high, although theoretical calculations predict that the chromophore remains quite planar.
However, in the more polar media, where the interactions are stronger, such planarity could
be slightly distorted, likely increasing the internal conversion relaxation with the consequent
reduction in the fluorescence ability. Alternatively, a further addition of aromatic rings to the
chromophoric core could increase the charge separation, enhancing the non-radiative
deactivation pathways in polar media.
ACS Paragon Plus Environment

Page 25 of 63
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Laser Properties
In view of the high fluorescence efficiency of these red-emitting dyes, we tested their
performance as active media for tunable lasers (see methods in ESI). Owing to the limited
solubility of some of the dyes in apolar media, we chose ethyl acetate as the right solvent to
measure the laser properties. In addition, this solvent allows assessing the prospects of doping
these dyes into solid-state dye lasers (SSDL), as it mimics the chemical structure of methyl
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
4
3
methacrylic polymers. Hence, the laser characterization and optimization in ethyl acetate
could be directly extrapolated to these polymers. Even so, in the most functionalized and
largest dyes the solubility was restricted to 0.5 mM (37 and 41) or the required concentration
to attain laser emission could not be reached (42).
Table 6. Laser properties of red-emitting benzofuran-fused BODIPYs in ethyl acetate at the
optimum dye concentration. The full set of laser data as a function of dye concentration are
listed in Table S3. The data corresponding to the commercially available red-emitting
BODIPY laser dye (PM650) are included for comparison.
Dye
[Dye] Effa λpeak (nm)
(mM) (%)
Edose90%
(GJ/mol)
22
23
0.75
0.50
0.50
1.00
0.75
1.25
1.25
0.75
0.50
0.50
44
48
28
45
44
43
43
43
27
40
31
646.5
648.8
636.0
645.2
647.2
642.0
657.6
656.2
685.0
650.0
656.5
2.14
3.30
1.07
0.96
1.94
7.39
5.26
4.24
4.46
1.96
6.29
2
2
2
3
3
3
3
4
4
5
6
4
5
6
7
1
PM650 1.00
a
90%
Eff: Laser efficiency or ratio of output/input energy; λpeak: Laser peak wavelength; Edose
Molar energy dose needed to reduce LIF to a 90% of its initial value (see methods for a
:
detail description).
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 26 of 63
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
The laser properties correlate, grosso modo, with the photophysical signatures (Table 5 and
S1). At high concentrations, all the dyes (with the aforementioned exception of 42 owing to
solubility reasons) display a laser emission line far away from the absorption and
fluorescence band (around 70 and 50 nm, respectively), much stronger than what is usually
recorded for BODIPY dyes (around 40 and 20 nm, respectively).44 In particular, dye 37
presents the redder laser band, which is centered at 685 nm thanks to its higher number of
aromatic rings fused to the chromophoric core (Figure 8). In contrast, at low concentrations
or low pump energies, the laser emission band appears in the expected position for BODIPYs
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(
Figure 8), leading, in some cases, to bichromatic emission (Figure 11 and Table S3). Such
dual laser emission has been previously ascribed to the formation of excited state aggregates
excimers or super-exciplexes) under strong laser pumping conditions of high optical density
(
4
5
active media, hence it is absent in the photophysical measurements. In this sense, the laser
band recorded for these dyes at high concentrations in ethyl acetate corresponds to an
aggregated form of the dyes, whereas the blue-shifted laser band at low concentrations
corresponds to the dye in monomeric form (Figure 11). The presence of this kind of
aggregates also enables widening the tuning range.45b
ACS Paragon Plus Environment

Page 27 of 63
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Figure 11. Normalized laser spectra (left) and output energy (right) as a function of pump
energy for dye 25 0.38 mM in ethyl acetate.
With regard to the laser efficiencies, those dyes which showed high fluorescence efficiency
regardless of the surrounding media (22, 23, 25, 26, 34, 36 and 41) display high laser
efficiencies (surpassing the 40% at the optimal concentration). On the other hand, those dyes
which rendered the lowest fluorescence efficiencies (24 and 37) show accordingly the worst
laser efficiency (lower than 30%). The only exception to such good correlation is dye 35,
which underwent an ICT process. Indeed, in spite of its low fluorescence response, the
recorded laser efficiency for 35 places this compound amongst the best ones in this study.
Such apparent mismatch can be rationalized considering the shorter excited-state lifetime of
such dye, which favors the stimulated radiative deactivation and compensates for the low
spontaneous emission probability. An analogous behavior was reported previously for
LDS722, a hemicyanine dye with a quantum yield as low as 14% but a 43% laser efficiency
4
6
owing to a lifetime of around 500 ps. Most of the dyes show a good tolerance to a prolonged
and intense laser pumping, with the exception of the dyes bearing methoxy (25 and 41) or
formyl (24) functional groups at para position of the 8-phenyl ring. Indeed, more than 3
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 28 of 63
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
GJ/mol are required to decrease the laser output energy to a 90% of its initial value,
outstanding the fluorinated dye 34, which is able to tolerate up to 7.4 GJ/mol before the same
energy loss is recorded (Table 6). These results are consistent with a previously reported
strategy based on the fluorination of organic dyes, which enabled achieving long lasting
active media even under drastic pumping regime.47
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
To put these results into perspective, we compared the laser performance of these red emitting
laser dyes with that of the commercially available BODIPY PM650, consisting of a
methylated dipyrrin core with a cyano group at the meso position, that emits in the same
4
3
spectral region. This dye is very photostable (tolerance up to 6.3 GJ/mol) owing to the
electron withdrawing character of the said cyano group, which reduces the reactivity against
48
the oxidizing ambient oxygen, involved in the photodegradation mechanism. At the same
time, such functionalization enables the population of ICT states. Such non-radiative
deactivation channel shortens the lifetime, supporting the recorded moderately high laser
efficiencies (30%, Table 6) in spite of its reduced fluorescence efficiency. The photostability
of most of the herein tested dyes are lower than that of PM650, albeit some of them to reach
close values, outstanding dye 34 whose photostability even surpasses that of the reference
PM650. On the other hand, the recorded laser efficiencies of most of the herein tested dyes
(mainly, 22, 23, 25, 26, 34, 36 and 41) improve that displayed by PM650. Therefore, the
herein reported benzofuran-fused BODIPYs are suitable candidates to develop efficient red-
emitting lasers with a reasonable photostability.
Conclusions
We have described a novel synthetic methodology to prepare benzofuran-fused BODIPY
dyes in four steps starting from commercially available 8-methylthioBODIPY 4. Careful
ACS Paragon Plus Environment

Page 29 of 63
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
selection of the reaction conditions permitted the chemoselective functionalization of the
meso-position of multiply functionalized BODIPY 6. S Ar-like reaction of phenolates
N
exclusively at the 3- and 5-positions allow the positioning of such moiety for the final
intramolecular Pd(0)-catalyzed arylation at the 2- and 6-positions of the BODIPY nucleus.
The herein reported synthetic avenue allows not only an easy access to benzofuran-fused
BODIPYs with different substitution pattern, but also enables to incorporate relevant
biomolecules to the BODIPYs core. Once these biomolecules are endowed with new
fluorescent properties, they may find very interesting biology-related applications such as
sensors, cell-imaging, protein-labeling, and so on. The extended aromatic framework of these
conformationally restricted BODIPYs renders strong absorption, fluorescence and laser
bands shifted to the red edge of the visible. Indeed, the fluorescence and laser efficiencies
reach almost the 100% and are above 40%, respectively, in the best cases. It is worthy to note
that the laser emission is rather intriguing displaying a deep shift towards the red edge owing
to the promotion of excited state aggregates at high concentration and under intense laser
pumping. Therefore, these -extended BODIPYs show nice behavior as red laser dyes in
terms of efficiency and photostability, since up to 7.3 GJ per mol of dye are required to induce
a decrease of the output laser emission of just a 10%, overcoming the limitations of most of
the commercially available dyes (such as cyanines or oxazines) in such spectral region. This
method is amenable to grafting other heterocycles such as indoles and benzothiophenes by
adding either anilines or thiophenols. We are currently exploring these possibilities as well
as the cell-imaging properties of both 41 and 42. The results will be reported in due course.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Experimental
ACS Paragon Plus Environment