Near-infrared BODIPY dyes modulated with spirofluorene moieties

Article abstract of DOI:10.1016/j.tet.2011.02.073

New structurally constrained BODIPY dyes having electron-donating substituents were synthesized. As the key compounds for the construction of the BODIPY dyes, 1′H-spiro-[fluorene-9,4′-indeno[1,2-b]pyrrole] (sp-FIP) derivatives with electron-donating group

Full text of DOI:10.1016/j.tet.2011.02.073

Tetrahedron 67 (2011) 3105e3110
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Near-infrared BODIPY dyes modulated with spirofluorene moieties
*
Toshiyuki Kowada, Shuhei Yamaguchi, Hiroki Fujinaga, Kouichi Ohe
Department of Energy and Hydrocarbon Chemistry, Graduate School of Engineering, Kyoto University, Katsura, Nishikyo-ku, Kyoto 615-8510, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
New structurally constrained BODIPY dyes having electron-donating substituents were synthesized. As
the key compounds for the construction of the BODIPY dyes, 10H-spiro-[fluorene-9,40-indeno[1,2-b]
pyrrole] (sp-FIP) derivatives with electron-donating groups, such as OMe and NMe2 at its 60-position,
were prepared using palladium-catalyzed intramolecular direct CeH arylation of a pyrrole moiety. The
resulting BODIPY dyes showed bathochromic shift in absorption and fluorescence spectra in comparison
to the unsubstituted analogs. Furthermore, pH-dependent reversible spectrum changes of the BODIPY
dye were observed with the addition of trifluoroacetic acid (TFA) and subsequent addition of i-Pr2NEt.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 27 January 2011
Received in revised form 22 February 2011
Accepted 24 February 2011
Available online 2 March 2011
Keywords:
BODIPY dye
Fluorescence
Near-infrared
CeH arylation
Charge transfer
1. Introduction
Ar
Ar
B
4,4-Difluoro-4-bora-3a,4a-diaza-s-indacenes (BODIPY) are at-
tractive fluorescent dyes because of their remarkable physical
properties, such as high photoluminescent quantum yields, large
molar absorption coefficients, narrow emission bands, and high
environmental stability.1 Therefore, they have been widely used in
a variety of organic functional materials where biological applica-
tions require light-emitting properties in the near-IR or visible red
region.2 To modulate the optical properties of BODIPY dyes, in par-
ticular, the following strategies are elaborated: (1) extension of
1
7
8
6
2
N
F
N
F
N
F
N
F
5
B
4
3
A: Ar = 4-I-C6H4-
λabs 555 nm, λem 588 nm, Φ F 0.20
D: Ar = 4-Tolyl
λabs 626 nm, λem 639 nm, ΦF 0.92
Ar
Ar
p
-conjugation by introducing aryl3 or styryl4 substituents at the 3,5-
N
F
N
F
N
F
N
F
positions; (2) rigidifying the molecular structure tosuppressthe free
rotation of extended substituents and enhance the coplanarity;5 and
(3) introducing electron-donating groups at the 3,5-positions.5e8 In
particular, the third approach is the most effective for the red shift of
both the absorption and the emission spectra. Burgess et al. in-
vestigated the phenyl- or p-anisyl-substituted BODIPY dyes (A and
B) and found that the introduction of the electron-donating
methoxy groups led to the red shift of the spectra by about 30 nm
(Fig. 1, A: lem 588 nm, B: lem 626 nm).6a Similar phenomena have
B
B
MeO
OMe
MeO
OMe
B:
E:
Ar = 4-HO-C6H4-
λabs 647 nm, λem 653 nm, ΦF 0.73
Ar = 4-I-C6H4-
λabs 582 nm, λem 626 nm, Φ F 0.42
Ar
Ar
been observed in styryl-substituted BODIPY dyes D4a
and E6b
lem 653 nm). Ziessel et al. reported that strong electron-
(lem 639 nm)
N
F
N
F
N
F
N
F
B
B
(
donating p-aminostyryl groups have great potential to give a bath-
ochromic shift of about 80 nm (Fig. 1, F: lem 767 nm).6c In addition,
applications in fluorescent sensors of pH7 and/or metal ions8,9 take
advantage of the basicity or coordination of amino groups. However,
Me2N
NMe2
Me2N
NMe2
C: unknown
F: Ar = 4-I-C6H4
-
λabs 706 nm, λem 767 nm, ΦF 0.18
* Corresponding author. Tel.: þ81 75 383 2495; fax: þ81 75 383 2499; e-mail
address: ohe@scl.kyoto-u.ac.jp (K. Ohe).
Fig. 1. The photophysical properties of 3,5-diaryl or distyryl-substituted BODIPY dyes.
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.02.073

3106
T. Kowada et al. / Tetrahedron 67 (2011) 3105e3110
p-aminophenyl-substituted BODIPY dyes (type C) have not so far
been explored.
We next examined the transformation of sp-FIP derivatives to
BODIPY dyes (Schemes 2 and 3). MeO-sp-FIP was reacted with
methyl 4-formylbenzoate to give dipyrromethane, which was sub-
sequently oxidized and complexed with BF3$OEt2, leading to the
formation of BODIPY dye 5a. Although we attempted to prepare 5b
using Me2N-sp-FIP in a similar manner, the oxidation using DDQ or
p-chloranil resulted in decomposition or recovery of the corre-
sponding dipyrromethane. Thus, we changed the synthetic route to
5b (Scheme 3). Acylpyrrole 6 was prepared by the reaction of Me2N-
sp-FIP with methyl 4-(chlorocarbonyl)benzoate in 52% yield, and
then the condensation of 6 with 1 equivof Me2N-sp-FIP, followed by
complexation with BF3$OEt2 led to the desired BODIPY dye 5b.
We recently reported that structurally constrained BODIPY dyes
that were synthesized using the strategies 1 and 2 shown above
exhibited intense fluorescence with the emission maxima around
670 nm (Fig. 2).10 We also described solvent-dependent fluores-
cence of the BODIPY dye with p-aminophenyl substituents at the 8-
positions, which was caused by photoinduced electron transfer
(PeT).10,11 We now report the synthesis of structurally constrained
BODIPY dyes with p-anisyl or p-aminophenyl substituents at the
3,5-positions (types B and C).
R
CO Me
H
N
1) p-chloranil
CH Cl , 0 °C, 1 h
CHO
, TFA
MeO
N
F
N
F
B
CH Cl2
2) BF ·OEt2, iPr NEt
0 °C, 2 h
0 °C, 3 h
MeO-sp-FIP
Fig. 2. Structurally constrained BODIPY dyes.
(2 equiv)
CO Me
2. Results and discussion
The preparations of 60-methoxy-10H-spiro[fluorene-9,40-indeno-
[1,2-b]pyrrole] (MeO-sp-FIP) and 60-(N,N-dimethylamino)-10H-spiro
[fluorene-9,40-indeno[1,2-b]pyrrole] (Me2N-sp-FIP) as key com-
pounds for the synthesis of structurally constrained BODIPY dyes are
summarized in Scheme 1. The reaction of 1-bromo-2-iodo-4-
methoxybenzene (1a) and 4-bromo-3-iodo-N,N-dimethylaniline
(1b) with isopropyl Grignard reagent followed by quenching with
9-fluorenone gave 2a and 2b in 81% and 77% yield, respectively.
FriedeleCrafts alkylation of N-tosylpyrrole with 2a and 2b using
AlCl3 afforded 3a and 3b in 97% and 70% yield, respectively. The
catalytic intramolecular direct CeH arylation10,12 of 3a using Pd-
(PPh3)4 proceeded smoothly to afford 4a in 60% yield. From 3b, 4b
was obtained in 35% yield using Pd2(dba)3 and P(t-Bu)3 instead of
Pd(PPh3)4. Detosylation of 4 using tetrabutylammonium fluoride
(TBAF) gave sp-FIP derivatives, MeO-sp-FIP and Me2N-sp-FIP, in
excellent yields (quantitative yield and 87%, respectively).13
N
F
N
F
B
MeO
OMe
5a 36% (for three steps)
Scheme 2.
CO Me
CO Me
COCl
H
N
Me N
O
N
H
CH Cl
reflux, 12 h
Me N
Br
1) iPrMgBr, THF
-40 °C, 3 h
Me N-sp-FIP
6
52%
Br
I
OH
R
R
2) 9-fluorenone
-40 °C to rt, 12–15 h
CO Me
(1.5 equiv)
1a (R = OMe)
2a
1) Me N-sp-FIP
POCl , CH Cl
reflux, 39 h
81%
1b
2b 77%
(R = NMe2)
Pd(PPh3)4 (3 mol%)
or
Pd2(dba)3 (2.5 mol%)
P(tBu)3 (10 mol%)
N
F
N
B
·
F
2) BF OEt
Ts
Br
N
iPr NEt, rt, 2 h
N
Ts
, AlCl3
Me N
NMe
R
K2CO3 (2 equiv), DMF
100 °C, 19–96 h
CH2Cl2
rt, 3–4 h
5b 39% (for two steps)
Scheme 3.
3a
97%
3b 70%
The absorption and emission spectra of 5a and 5b were mea-
sured in THF (Table 1). The absorption maximum and the emission
maximum of 5a were red-shifted by about 30 nm compared with
those of 5c without electron-donating groups. Furthermore, 5a
showed intense fluorescence (FF¼0.61) with a small Stokes shift
(15 nm) because of its rigid structure. Because of the strong elec-
tron-donating ability of N,N-dimethylamino groups, 5b exhibited
bathochromic shifts of about 80 nm in both absorption and emis-
sion maxima compared with 5c. However, 5b showed lower
Ts
N
H
N
TBAF
R
R
THF, reflux
14–22 h
4a 60%
4b 35%
MeO-sp-FIP quant
Me2N-sp-FIP 87%
Scheme 1.

T. Kowada et al. / Tetrahedron 67 (2011) 3105e3110
3107
Table 1
solution of 5b (Fig. 4). In the absorption spectra, the initial ab-
sorption band at 741 nm decreased and a distinctive sharp ab-
sorption band of a BODIPY dye appeared at 636 nm, which can
correspond to 5b-2Hþ ([TFA]¼1 M, Fig. 4). The emission spectra
showed a parallel change with the absorption spectra. The original
broad fluorescence band of 5b changed with blue shift as TFA was
added, and a sharp and strong emission peak arose at 647 nm when
the TFA concentration reached 1 M. This indicates that the pro-
tonated amino groups no longer act as electron-donors. Then, to
prove that the phenomenon is caused by the protonation on amino
groups rather than such structural changes as hydrolysis of the
ester group or deboronation, i-Pr2NEt was added to the acidic so-
lution (5b with [TFA]¼1 M). As expected, the identical spectra of
the original 5b were restored (Fig. 4). Thus, it is obvious that ICT
between amino groups and boron atom is inhibited by the pro-
tonation on amino groups.
In conclusion, we have developed structurally constrained
BODIPY dyes with electron-donating groups, such as MeO or Me2N
at the para position of phenyl groups substituted at 3,5-positions on
the BODIPY core. Palladium-catalyzed intramolecular direct CeH
arylation of a pyrrole moiety allowed us to synthesize sp-FIP de-
rivatives as the key compounds for the construction of the BODIPY
dyes. The emission bands of the resulting BODIPY dyes were shifted
bathochromically in comparison to unsubstituted analogs because
of the electron donation from the MeO and Me2N groups. In addi-
tion, amino-substituted BODIPY dye 5b showed ICT character. The
ICT process could be modulated by protonation on amino groups
and recovery of original absorption and fluorescence upon depro-
tonation with an additional base was demonstrated. We envision
the application of 5b in pH and/or metal ion sensors and further
investigations will be reported in due course.
Photophysical properties of BODIPY dyes 5aec in THF (c¼1.00ꢀ10ꢁ6 M)
CO2Me
N
F
N
F
B
R
R
5a–c
[Mꢁ1 cmꢁ1
]
lex [nm]
lem [nm]
FF
a
R
labs [nm]
3
5a
OMe
NMe2
H
666
738
641
159,000
133,000
161,100
666
733
640
681
769
652
0.61
0.24
0.67
5b
5cb
a
Determined by the calibrated integrating sphere system.
Ref. 10.
b
quantum yield (FF¼0.30) with larger Stokes shift (31 nm) than 5a
and 5c. This indicates the occurrence of intramolecular charge
transfer (ICT)7,8,14 in 5b.
When the absorption spectra of 5b were measured in various
solvents, the positions of the absorption maxima were slightly af-
fected by the solvent polarity (Fig. 3, Table 2). In contrast, the fea-
tures of solvent-dependent fluorescence of 5b were found in the
emission spectra. The emission maximum obviously shifts to
a longer wavelength, and the emission spectra were broadened and
weakened by going from nonpolar to polar solvents (cyclohexane:
741 nm; DMF: 792 nm). Furthermore, in cyclohexane, 5b showed
sharp and narrow emission spectrum with the highest fluorescence
quantum yield (FF¼0.51).
Fig. 3. The absorption (left) and emission spectra (right) of 5b in various solvents.
Table 2
Photophysical properties of BODIPY dyes 5b in various solvents (c¼1.00ꢀ10ꢁ6 M)
3. Experimental section
3.1. General
[Mꢁ1 cmꢁ1
]
lex
lem
FF
a
Solvent
labs
3
[nm]
[nm]
[nm]
Cyclohexane
Benzene
THF
MeCN
DMF
724
743
738
741
752
152,500
147,800
133,000
89,340
714
732
733
741
741
741
769
769
783
792
0.44
0.37
0.24
0.23
0.11
Unless otherwise specified, all reagents were purchased from
a chemical supplier and used without further purification. Tetra-
hydrofuran (THF) was distilled over benzophenone ketyl under
nitrogen atmosphere. N,N-Dimethylformamide (DMF) was distilled
over CaH2 under nitrogen atmosphere. CH2Cl2 was dried and col-
lected using a Grubbs-type solvent purification system manufac-
115,800
a
Determined by the calibrated integrating sphere system. Corrected for back-
ground noise at around 820 nm.
tured by Glass Contour. Melting points are uncorrected. 1H and 13
C
In general, the emission properties of the ICT fluorophores
having amino groups can be modulated by cation binding, which
reduces the electron-donating ability of the nitrogen atom. As
a result, ICT process is prohibited and the inherent sharp emission
of the BODIPY dye is restored. We next added TFA to the acetonitrile
spectra were recorded on a JEOL AL-300 (300 MHz for 1H and
75.5 MHz for 13C) instrument or a JEOL EX-400 (400 MHz for 1H and
100 MHz for 13C) instrument. IR spectra were obtained on a JASCO
460 plus FT/IR spectrometer. Mass spectra were measured with
a JEOL JMS-SX102A. Analytical thin-layer chromatography (TLC)

3108
T. Kowada et al. / Tetrahedron 67 (2011) 3105e3110
Fig. 4. The absorption spectra (left) and the emission spectra (right) of 5b after an addition of i-Pr2NEt.
was performed on Merck 60 F254 silica plates and visualized by UV
light. Column chromatography was carried out on Silicycle Silica-
overlapped). Anal. Calcd for C20H15O2Br: C, 65.41; H, 4.12. Found:
C, 65.18; H, 3.92.
Flash F60 60e63 mm (230e400 mesh) silica gel. UVevis absorption
spectra were recorded on a JASCO V-570 UVeviseNIR spectrome-
ter. Emission spectra were measured with a Jobin Yvon-Horiba
FluoroMax-3. Degassed spectral grade solvents were used for the
measurements. Absolute fluorescence quantum yields were de-
termined by the calibrated integrating sphere system.
3.2.3. 9-(2-Bromo-5-(dimethylamino)phenyl)-9H-fluoren-9-ol
(2b). The solution of 1b (3.42 g, 10.5 mmol) in dry THF (10 mL) was
cooled to ꢁ40 ꢂC. To the solution was added dropwise 1.0 M THF
solution of isopropyl magnesium bromide (15 mL), prepared from
isopropyl bromide and magnesium turnings. After stirring for 4 h, 9-
fluorenone (1.26 g, 7.00 mmol) in dry THF (10 mL) was added and
stirred at room temperature for 17 h. The reaction mixture was
quenched with saturated aqueous solution of NH4Cl (20 mL) and
extracted with EtOAc (3ꢀ10 mL). The organic layers were combined,
washed with brine (2ꢀ30 mL), and dried over MgSO4. The solvents
were removed under reduced pressure, the residue was purified
with column chromatography on SiO2 with EtOAc/hexane (v/v¼1/
10) as an eluent to give 2b (1.91 g, 72%) as a white solid; mp
161.9e162.8 ꢂC. IR (KBr) 733, 746, 770, 1149, 1361, 1446, 1491, 1591,
3.2. Syntheses
3.2.1. 4-Bromo-3-iodo-N,N-dimethylaniline (1b). To
a solution of
4-bromo-3-iodoaniline15 (12.8 g, 42.9 mmol) in DMF (120 mL) was
added K2CO3 (23.7 g, 172 mmol) and MeI (6.42 mL, 103 mmol), and
the solution was stirred at 70 ꢂC for 13 h. After cooling to ambient
temperature, water (180 mL) was added and the solution was
extracted with Et2O (5ꢀ40 mL). The organic layers were combined,
washed with brine (3ꢀ100 mL), and dried over MgSO4. The solvents
were removed under reduced pressure to give brown solid. The
crude product was purified by recrystallization from EtOAc/hexane
(v/v¼1/4) to give 1b (10.5 g, 75%) as a pale brown solid; mp
93.8e94.8 ꢂC. IR (KBr) 580, 797, 827, 955, 1231, 1362, 1496, 1582,
2808, 2879, 3457 cmꢁ1. 1H NMR (400 MHz, CDCl3):
d
¼2.40 (br s,1H),
3.03 (s, 6H), 6.51 (dd, J¼3.4, 8.8 Hz, 1H), 7.19e7.25 (m, 5H), 7.37 (dd,
J¼7.3, 8.3 Hz, 2H), 7.66 (d, J¼7.3 Hz, 2H), 7.87 (br s, 1H). 13C NMR
(100 MHz, CDCl3):
d
¼40.7,106.9,113.1,113.3,120.1,124.0,128.3,129.1,
134.6, 140.6, 141.3, 149.0, 149.6 (two peaks are overlapped). HRMS
(FAB): calcd for C21H1879BrNO (Mþ), 379.0572. Found 379.0564.
2810, 2889 cmꢁ1.1H NMR (300 MHz, CDCl3):
d
¼2.90 (s, 6H), 6.54 (dd,
J¼2.9, 8.8 Hz, 1H), 7.15 (d, J¼3.3 Hz, 1H), 7.35 (d, J¼8.8 Hz, 1H). 13C
3.2.4. 3-(9-(2-Bromo-5-methoxyphenyl)-9H-fluoren-9-yl)-N-to-
sylpyrrole (3a). To a solution of 2a (372 mg, 1.01 mmol) and N-
tosylpyrrole (248 g, 1.12 mmol) in CH2Cl2 (30 mL) was added AlCl3
(171 mg, 1.28 mmol) portionwise, and the solution was stirred at
room temperature for 3 h. The reaction mixture was quenched with
water (20 mL) and extracted with CH2Cl2 (3ꢀ10 mL). The organic
layers were combined, washed with saturated aqueous solution of
NaHCO3 (2ꢀ20 mL) and brine (2ꢀ20 mL), and dried over MgSO4.
The solvents were removed under reduced pressure, and the resi-
due was purified with column chromatography on SiO2 with EtOAc/
hexane (v/v¼1/6) as an eluent to give 3a (559 g, 97%) as a white
solid; mp 205.8e206.6 ꢂC. IR (KBr) 592, 675, 745, 796, 1067, 1173,
NMR (75.5 MHz, CDCl3):
d¼40.3,101.7,113.8,115.1,123.5,132.2,150.0.
Anal. Calcd for C8H9NBrI: C, 29.48; H, 2.78. Found: C, 29.39; H, 2.51.
3.2.2. 9-(2-Bromo-5-methoxyphenyl)-9H-fluoren-9-ol (2a). The
solution of 1-bromo-2-iodo-4-methoxybenzene (1a)16 (14.1 g,
45.0 mmol) in dry THF (45 mL) was cooled to ꢁ40 ꢂC. To the so-
lution was added dropwise 1.0 M THF solution of isopropyl
magnesium bromide (45 mL), prepared from isopropyl bromide
and magnesium turnings. After stirring for 4 h, 9-fluorenone
(6.34 g, 35.2 mmol) in dry THF (35 mL) was added over 15 min
and stirred at room temperature for 18 h. The reaction mixture
was quenched with saturated aqueous solution of NH4Cl (100 mL)
and extracted with EtOAc (3ꢀ30 mL). The organic layers were
combined, washed with brine (2ꢀ50 mL), and dried over MgSO4.
The solvents were removed under reduced pressure to give a pale
yellow solid. The crude product was purified by washing with
CHCl3/hexane (v/v¼1/3) to give 1a (10.5 g, 81%) as a white solid;
mp 217.8e218.5 ꢂC. IR (KBr) 734, 771, 1009, 1029, 1288, 1462, 1572,
1367, 1465, 1595, 3119, 3134 cmꢁ1 1H NMR (300 MHz, CDCl3):
.
d
¼2.37 (s, 3H), 3.60 (s, 3H), 6.42 (dd, J¼1.8, 3.3 Hz, 1H), 6.60e6.63
(m, 2H), 6.85 (br s, 1H), 7.08 (dd, J¼2.2, 3.3 Hz, 1H), 7.20e7.40 (m,
9H), 7.61 (d, J¼8.4 Hz, 2H), 7.72 (d, J¼7.3 Hz, 2H). 13C NMR
(75.5 MHz, CDCl3):
d
¼21.6, 55.1, 60.4, 113.3, 113.4, 115.6, 118.8, 119.3,
120.4, 121.5, 124.6,126.8, 127.4,127.6, 129.9, 131.8, 135.9,136.0, 141.1,
143.1, 144.8, 149.6, 158.3. HRMS (FAB): calcd for C31H2581BrNO3S
(MþHþ), 572.0722. Found 572.0733.
1598, 2939, 3066, 3437 cmꢁ1. 1H NMR (300 MHz, CDCl3):
d
¼2.40
(br s, 1H), 3.91 (s, 3H), 6.72 (dd, J¼3.3, 8.8 Hz, 1H), 7.15e7.30 (m,
5H), 7.39 (dd, J¼7.3, 7.3 Hz, 2H), 7.67 (d, J¼7.7 Hz, 2H), 8.06 (br s,
1H). 13C NMR (75.5 MHz, CDCl3):
124.0, 128.4, 129.3, 135.0, 141.4, 141.9, 148.6, 158.8 (two peaks are
d
¼55.5, 111.1, 114.6, 115.1, 120.2,
3.2.5. 3-(9-(2-Bromo-5-(dimethylamino)phenyl)-9H-fluoren-9-yl)-N-
tosylpyrrole (3b). To a solution of 2b (188 mg, 0.494 mmol) and N-

T. Kowada et al. / Tetrahedron 67 (2011) 3105e3110
3109
tosylpyrrole (116 mg, 0.525 mmol) in CH2Cl2 (5 mL) was added AlCl3
(90.3 mg, 0.677 mmol) portionwise, and the solution was stirred at
room temperature for 4 h. The reaction mixture was quenched with
water (20 mL) and extracted with CH2Cl2 (3ꢀ5 mL). The organic
layers were combined, washed with saturated aqueous solution of
NaHCO3 (2ꢀ20 mL) and brine (2ꢀ20 mL), and dried over MgSO4. The
solvents were removed under reduced pressure, and the residue was
purified with column chromatography on SiO2 with EtOAc/hexane
(v/v¼1/2) as an eluent to give 3b (199 mg, 70%) as a white solid; mp
and THF was removed under reduced pressure. The residue was
extracted with CH2Cl2 (3ꢀ15 mL). The organic layers were com-
bined, washed with brine (2ꢀ50 mL), and dried over MgSO4. The
solvents were removed under reduced pressure, the residue was
purified with column chromatography on SiO2 with CH2Cl2/hexane
(v/v¼1/1) as an eluent to give MeO-sp-FIP (1.34 g, quantitative
yield) as a pale pink solid; mp 156.9e157.8 ꢂC. IR (KBr) 742, 1274,
1444, 1461, 1587, 3063, 3418 cmꢁ1 1H NMR (300 MHz, CDCl3):
.
d
¼3.58 (s, 3H), 5.77 (br s, 1H), 6.13 (d, J¼2.2 Hz, 1H), 6.71e6.76 (m,
216.0e216.8 ꢂC. IR (KBr) 676, 743, 1063, 1173, 1371, 1593 cmꢁ1
.
1H
2H), 6.85 (d, J¼7.7 Hz, 2H), 7.11 (dd, J¼7.3, 7.7 Hz, 2H), 7.23 (d,
J¼8.4 Hz,1H), 7.33 (dd, J¼7.3, 7.7 Hz, 2H), 7.80 (d, J¼7.7 Hz, 2H), 8.33
NMR (300 MHz, CDCl3):
d
¼2.38 (s, 3H), 2.68 (s, 6H), 6.41 (dd, J¼3.3,
8.8 Hz,1H), 6.45 (br s,1H), 6.60 (br s,1H), 7.08 (dd, J¼2.6, 2.9 Hz, 1H),
(br s, 1H). 13C NMR (75.5 MHz, CDCl3):
d¼55.4, 60.8, 103.9, 111.1,
7.16e7.39 (m, 9H), 7.62 (d, J¼8.1 Hz, 2H), 7.72 (d, J¼7.3 Hz, 2H). 13C
111.6, 116.1, 119.8, 120.9, 123.8, 127.4, 127.6, 128.7, 132.4, 137.6, 141.6,
148.7, 155.1, 157.3. HRMS (FAB): calcd for C24H18NO (MþHþ),
336.1388. Found 336.1371.
NMR (75.5 MHz, CDCl3):
d
¼21.6, 40.1, 60.6, 109.0, 112.6, 116.0, 116.9,
119.3, 120.3, 121.3, 124.7, 126.7, 127.3, 127.5, 129.8, 132.4, 135.4, 136.2,
141.1, 141.9, 144.7, 149.1, 150.0. HRMS (FAB): calcd for
C32H2879BrN2O2S (MþHþ), 583.1055. Found 583.1057.
3.2.9. 60-(N,N-Dimethylamino)-10H-spiro[fluorene-9,40-indeno-[1,2-
b]pyrrole] (Me2N-sp-FIP). To a solution of 4b (736 mg, 1.46 mmol)
in THF (2 mL) was added 1.0 M THF solution of TBAF (14.6 mL),
and the solution was stirred at 65 ꢂC for 22 h under nitrogen
atmosphere. After cooling to ambient temperature, water (40 mL)
was added and THF was removed under reduced pressure. The
residue was extracted with CH2Cl2 (3ꢀ10 mL). The organic layers
were combined, washed with brine (2ꢀ40 mL), and dried over
MgSO4. The solvents were removed under reduced pressure, the
residue was purified with column chromatography on SiO2 with
CH2Cl2/hexane (v/v¼1/1) as an eluent to give Me2N-sp-FIP
(441 mg, 87%) as a pale green solid; mp 178.2 ꢂC (dec). IR (KBr)
737, 797, 1440, 1488, 1582, 3396 cmꢁ1. 1H NMR (300 MHz, CDCl3):
3.2.6. 60-Methoxy-10-tosyl-10H-spiro[fluorene-9,40-indeno[1,2-b]pyr-
role] (4a). A flame dried flask was charged with 3a (6.85 g,
12.0 mmol), K2CO3 (3.32 g, 24.0 mmol), Pd(PPh3)4 (417 mg,
0.361 mmol), and dry DMF (100 mL) under nitrogen atmosphere.
The solution was stirred at 100 ꢂC for 13 h. The reaction mixture
was cooled down to room temperature and filtered through a short
silica gel pad. After an addition of CH2Cl2 (100 mL), the filtrate was
washed with brine (6ꢀ150 mL), and dried over MgSO4. The solvents
were removed under reduced pressure to give a brown solid. The
crude product was purified by washing with CHCl3/hexane (v/v¼1/
3) to give 4a (3.93 g, 67%) as a pale green solid; mp 211.3e212.0 ꢂC.
IR (KBr) 539, 583, 679, 750, 1125, 1171, 1276, 1368, 1586, 3139 cmꢁ1
1H NMR (300 MHz, CDCl3):
.
d
¼2.71 (s, 3H), 5.73 (dd, J¼1.8, 2.6 Hz, 1H), 6.00 (d, J¼2.2 Hz, 1H),
d
¼2.42 (s, 3H), 3.60 (s, 3H), 5.83 (d,
6.56 (dd, J¼2.2, 8.1 Hz, 1H), 6.70 (dd, J¼2.2, 2.6 Hz, 1H), 6.87 (d,
J¼7.7 Hz, 2H), 7.11 (dd, J¼7.3, 7.3 Hz, 2H), 7.20 (d, J¼8.4 Hz, 1H),
7.32 (dd, J¼7.3, 7.7 Hz, 2H), 7.80 (d, J¼7.7 Hz, 2H), 8.28 (br s, 1H).
J¼3.3 Hz, 1H), 6.09 (d, J¼2.6 Hz, 1H), 6.64 (d, J¼7.7 Hz, 2H), 6.80 (dd,
J¼2.6, 8.4 Hz, 1H), 7.08 (dd, J¼6.6, 7.3 Hz, 2H), 7.14 (d, J¼2.9 Hz, 1H),
7.29e7.35 (m, 4H), 7.78 (d, J¼7.7 Hz, 2H), 7.81 (d, J¼8.4 Hz, 2H), 8.05
13C NMR (75.5 MHz, CDCl3):
d
¼41.0, 60.9, 103.7, 109.7, 110.8, 116.2,
(d, J¼8.4 Hz, 1H). 13C NMR (75.5 MHz, CDCl3):
d¼21.6, 55.3, 60.2,
119.7, 120.1, 123.9, 125.4, 127.2, 127.5, 131.4, 138.2, 141.5, 148.4,
149.5, 154.6. HRMS (FAB): calcd for C25H20N2 (Mþ), 348.1626.
Found 348.1631.
108.8, 110.7, 112.2, 120.0, 120.1, 123.6, 125.7, 126.7, 127.2, 127.7, 127.8,
130.0, 136.0, 138.2, 138.3, 141.7, 145.0, 146.7, 154.6, 158.2. HRMS
(FAB): calcd for C31H24NO3S (MþHþ), 490.1477. Found 490.1494.
3.2.10. BODIPY dye 5a. To a solution of MeO-sp-FIP (336 mg,
1.00 mmol) and methyl 4-formylbenzoate (81.8 mg, 0.50 mmol) in
dry CH2Cl2 (20 mL) was added two drops of TFA, and the solution
was stirred at 0 ꢂC for 2 h under nitrogen atmosphere. The reaction
mixture was quenched with saturated aqueous solution of NaHCO3
(20 mL) and extracted with CH2Cl2 (3ꢀ10 mL). The organic layers
were combined, washed with brine (2ꢀ25 mL), and dried over
MgSO4. The solvents were removed under reduced pressure, and
the residue was partially purified with column chromatography on
SiO2 with CH2Cl2 as an eluent to afford a crude product (220 mg)
as a purple solid. The crude product was then dissolved in dry
CH2Cl2 (10 mL). After an addition of p-chloranil (66.5 mg,
0.270 mmol) in dry CH2Cl2 (10 mL), the solution was stirred at 0 ꢂC
for 90 min under nitrogen atmosphere. i-Pr2NEt (0.231 mL,
1.33 mmol) and BF3$OEt2 (0.360 mL, 1.32 mmol) were successively
added and after 2 h, the reaction mixture was washed with 10%
aqueous solution of NaCl (3ꢀ30 mL), and dried over Na2SO4. The
solvents were removed under reduced pressure, and the residue
was purified with column chromatography on SiO2 with CH2Cl2 as
an eluent to afford 5a (152 mg, 36% yield based on MeO-sp-FIP) as
a dark brown solid; mp>300 ꢂC. IR (KBr) 745, 1060, 1176, 1260,
3.2.7. 60-(N,N-Dimethylamino)-10-tosyl-10H-spiro[fluorene-9,40-in-
deno[1,2-b]pyrrole] (4b). A flame dried flask was charged with 3b
(2.93 g, 5.02 mmol), K2CO3 (1.38 g, 10.0 mmol), Pd2(dba)3 (115 mg,
0.126 mmol), P(t-Bu)3 (103 mg, 0.510 mmol), and dry DMF (50 mL)
under nitrogen atmosphere. The solution was stirred at 100 ꢂC for
96 h. The reaction mixture was cooled down to room temperature
and filtered through a short silica gel pad. After an addition of
CH2Cl2 (50 mL), the filtrate was washed with brine (6ꢀ100 mL),
and dried over MgSO4. The solvents were removed under reduced
pressure, the residue was purified with column chromatography
on SiO2 with EtOAc/hexane (v/v¼1/6) as an eluent to give 4b
(897 mg, 35%) as a greenish brown solid; mp 199.6 ꢂC (dec). IR
(KBr) 576, 679, 743, 1122, 1174, 1371, 1432, 1606, 3130 cmꢁ1
.
1H
NMR (300 MHz, CDCl3):
d
¼2.41 (s, 3H), 2.73 (s, 6H), 5.78 (d,
J¼2.9 Hz, 1H), 5.91 (d, J¼2.6 Hz, 1H), 6.60e6.67 (m, 3H), 7.04e7.09
(m, 3H), 7.25e7.34 (m, 4H), 7.77 (d, J¼7.3 Hz, 2H), 7.81 (d, J¼8.4 Hz,
2H), 8.00 (d, J¼8.4 Hz, 1H). 13C NMR (75.5 MHz, CDCl3):
¼21.6,
d
40.6, 60.4, 108.5, 108.8, 111.0, 119.9, 120.0, 123.4, 123.7, 124.7, 126.8,
127.56, 127.61, 129.9, 136.1, 136.9, 138.9, 141.6, 144.7, 147.5, 149.0,
154.3. HRMS (FAB): calcd for C32H26N2O2S (Mþ), 502.1715. Found
502.1705.
1323, 1548, 1606, 1723, 3062 cmꢁ1 1H NMR (300 MHz, CDCl3)
.
d
¼3.67 (s, 6H), 3.82 (s, 3H), 6.03 (s, 2H), 6.14 (d, J¼2.2 Hz, 2H), 6.96
3.2.8. 60-Methoxy-10H-spiro[fluorene-9,40-indeno[1,2-b]pyrrole]
(MeO-sp-FIP). To a solution of 4a (1.96 g, 4.00 mmol) in THF
(300 mL) was added 1.0 M THF solution of TBAF (40 mL), and the
solution was stirred at 65 ꢂC for 14 h under nitrogen atmosphere.
After cooling to ambient temperature, water (40 mL) was added
(d, J¼7.3 Hz, 4H), 7.04 (dd, J¼2.6, 8.8 Hz, 2H), 7.16 (dd, J¼7.3, 7.7 Hz,
4H), 7.33e7.41 (m, 6H), 7.77 (d, J¼7.3 Hz, 4H), 7.87 (d, J¼8.1 Hz,
2H), 8.40 (d, J¼8.8 Hz, 2H). 13C NMR (75.5 MHz, CDCl3)
¼52.2,
d
55.6, 59.8, 109.9, 115.0, 119.3, 120.0, 124.2, 125.47, 125.53, 127.9,
128.0, 129.2, 130.3, 130.8, 138.1, 138.9, 140.2, 141.2, 142.9, 148.2,

3110
T. Kowada et al. / Tetrahedron 67 (2011) 3105e3110
159.3, 161.1, 162.2, 166.2. HRMS (FAB): calcd for C57H38O4N2F2B
Center for Integrated Research and Advanced Education in Mate-
rials Science’ (No. B-09) of MEXT, administrated by the JSPS.
(MþHþ), 863.2902. Found 863.2916.
3.2.11. 10-(4-(Methoxycarbonyl)benzoyl)-60-(N,N-dimethyl-amino)-
10H-spiro[fluorene-9,40-indeno[1,2-b]pyrrole] (6). To a solution of
Me2N-sp-FIP (108 mg, 0.310 mmol) in dry CH2Cl2 (8 mL) was added
methyl 4-(chlorocarbonyl)benzoate in dry CH2Cl2 (7 mL), and the
solution was stirred at 40 ꢂC for 12 h under nitrogen atmosphere.
After an addition of water (20 mL), the reaction mixture was
extracted with CH2Cl2 (3ꢀ5 mL). The organic layers were com-
bined, washed with brine (2ꢀ20 mL), and dried over MgSO4. The
solvents were removed under reduced pressure, and the residue
was purified with column chromatography on SiO2 with EtOAc/
CH2Cl2 (v/v¼1/20) as an eluent to afford 6 (82.6 mg, 52%) as a or-
ange solid; mp 163.5 ꢂC (dec). IR (KBr) 740, 1279, 1352, 1583, 1725,
Supplementary data
Supplementary data associated with this article can be found in
online version at doi:10.1016/j.tet.2011.02.073.
References and notes
1. (a) Loudet, A.; Burgess, K. Chem. Rev. 2007, 107, 4891e4932; (b) Ulrich, G.;
Ziessel, R.; Harriman, A. Angew. Chem., Int. Ed. 2008, 47, 1184e1201.
2. Lavis, L. D.; Raines, R. T. ACS Chem. Biol. 2008, 3, 142e155.
3. Wakamiya, A.; Sugita, N.; Yamaguchi, S. Chem. Lett. 2008, 37, 1094e1095.
4. (a) Rohand, T.; Qin, W.; Boens, N.; Dehaen, W. Eur. J. Org. Chem. 2006,
4658e4663; (b) Qin, W.; Rohand, T.; Dehaen, W.; Clifford, J. N.; Driesen, K.;
Beljonne, D.; Van Averbeke, B.; Van der Auweraer, M.; Boens, N. J. Phys. Chem. A
2007, 111, 8588e8597; (c) Dost, Z.; Atilgan, S.; Akkaya, E. U. Tetrahedron 2006,
62, 8484e8488.
3223 cmꢁ1. 1H NMR (300 MHz, CDCl3)
d¼2.78 (s, 6H), 3.91 (s, 3H),
5.92 (d, J¼2.2 Hz, 1H), 6.37 (s, 1H), 6.60 (dd, J¼2.2, 8.4 Hz, 1H), 6.91
(d, J¼7.3 Hz, 2H), 7.15 (dd, J¼7.3, 7.7 Hz, 2H), 7.36 (dd, J¼7.3, 7.7 Hz,
2H), 7.62 (d, J¼8.4 Hz, 1H), 7.80 (d, J¼7.7 Hz, 2H), 7.86 (d, J¼8.1 Hz,
2H), 8.04 (d, J¼8.1 Hz, 2H), 11.02 (s, 1H). 13C NMR (75.5 MHz, CDCl3)
5. (a) Chen, J.; Burghart, A.; Derecskei-Kovacs, A.; Burgess, K. J. Org. Chem. 2000, 65,
2900e2906; (b) Umezawa, K.; Nakamura, Y.; Makino, H.; Citterio, D.; Suzuki, K. J.
Am. Chem. Soc. 2008,130,1550e1551; (c) Wu, L.; Burgess, K. Chem. Commun. 2008,
4933e4935; (d) Mei, Y.; Bentley, P. A.; Wang, W. Tetrahedron Lett. 2006, 47,
2447e2449; (e) For aza-BODIPY derivatives, see: Zhao, W.; Carreira, E. M. Angew.
Chem., Int. Ed. 2005, 44, 1677e1679; (f) Zhao, W.; Carreira, E. M. Chem.dEur. J.
2006, 12, 7254e7263; (g) Loudet, A.; Bandichhor, R.; Burgess, K.; Palma, A.;
McDonnell, S. O.; Hall, M. J.; O’Shea, D. F. Org. Lett. 2008, 10, 4771e4774.
6. (a) Burghart, A.; Kim, H.; Weich, M.; Thoresen, L. H.; Reibenspies, J.; Burgess, K.;
d
¼40.4, 52.3, 60.6, 107.9, 111.4, 115.9, 119.9, 120.7, 121.2, 124.0, 127.6,
127.8, 128.7, 129.4, 132.0, 134.1, 134.9, 141.4, 143.2, 148.4, 148.8,
150.7, 157.0, 166.5, 182.2. HRMS (FAB): calcd for C34H27O3N2
(MþHþ), 511.2022. Found 511.2018.
ꢀ
€
Bergstrom, F.; Johansson, L. B.-A. J. Org. Chem. 1999, 64, 7813e7819; (b) Liu, J.-Y.;
Yeung, H.-S.; Xu, W.; Li, X.; Ng, D. K. P. Org. Lett. 2008, 10, 5421e5424; (c)
Ziessel, R.; Ulrich, G.; Harriman, A.; Alamiry, M. A. H.; Stewart, B.; Retailleau, P.
Chem.dEur. J. 2009, 15, 1359e1369; (d) Yamada, K.; Toyota, T.; Takakura, K.;
Ishimaru, M.; Sugawara, T. New J. Chem. 2001, 25, 667e669; (e) Buyukcakir, O.;
Bozdemir, O. A.; Kolemen, S.; Erbas, S.; Akkaya, E. U. Org. Lett. 2009, 11,
4644e4647.
3.2.12. BODIPY dye 5b. To a solution of 6 (77.2 mg, 0.151 mmol) and
Me2N-sp-FIP (53.1 mg, 0.152 mmol) in CH2Cl2 (4 mL) was added
POCl3 (18 m
l, 0.197 mmol), and the solution was stirred at 40 ꢂC for
39 h under nitrogen atmosphere. After cooling to ambient tem-
perature, the reaction mixture was quenched with saturated
aqueous solution of NaHCO3 (15 mL) and extracted with CH2Cl2
(3ꢀ5 mL). The organic layers were combined, washed with brine
(2ꢀ25 mL), and dried over Na2SO4. The solvents were removed
under reduced pressure, and the residue was partially purified with
column chromatography on SiO2 with CH2Cl2/EtOAc (v/v¼10/1) as
an eluent to afford a crude product (53.8 mg) as a dark green solid.
The crude product was then dissolved in CH2Cl2 (8 mL). i-Pr2NEt
(0.056 mL, 0.321 mmol) and BF3$OEt2 (0.087 mL, 0.320 mmol)
were added and the reaction mixture was stirred at room tem-
perature for 2 h. The reaction mixture was washed with 10%
aqueous solution of NaCl (3ꢀ20 mL), and dried over Na2SO4. The
solvents were removed under reduced pressure, and the residue
was partially purified with column chromatography on SiO2 with
CH2Cl2/EtOAc (v/v¼40/1) as an eluent to afford 5b (55.5 mg, 39%
yield based on 6) as a dark brown solid; mp>300 ꢂC. IR (KBr) 1019,
1057, 1276, 1313, 1541, 1602, 1727 cmꢁ1. 1H NMR (300 MHz, CDCl3)
7. (a) Rurack, K.; Kollmannsberger, M.; Daub, J. Angew. Chem., Int. Ed. 2001, 40,
385e387; (b) Coskun, A.; Denis, E.; Akkaya, E. U. Org. Lett. 2005, 7, 5187e5189; (c)
Bonardi, L.; Ulrich, G.; Ziessel, R. Org. Lett. 2008, 10, 2183e2186; (d) Deniz, E.;
Isbasar, G. C.; Bozdemir, OA.; Yildirim, L. T.; Siemiarczuk, A.; Akkaya, E. U. Org. Lett.
2008,10, 3401e3403; (e) Baruah, M.; Qin, W.; Flors, C.; Hofkens, J.; Vallee, R. A. L.;
Beljonne, D.; Van der Auweraer, M.; De Borggraeve, W. M.; Boens, N. J. Phys. Chem.
A 2006, 110, 5998e6009; (f) Saki, N.; Dinc, T.; Akkaya, E. U. Tetrahedron 2006, 62,
2721e2725; (g) Yu, Y.-H.; Descalzo, A. B.; Shen, Z.; Rohr, H.; Liu, Q.; Wang, Y.-W.;
Spieles, M.; Li, Y.-Z.; Rurack, K.; You, X.-Z. Chem.dAsian J. 2006, 1e2, 176e187.
8. (a) Peng, X.; Du, J.; Fan, J.; Wang, J.; Wu, Y.; Zhao, J.; Sun, S.; Xu, T. J. Am. Chem.
Soc. 2007, 129, 1500e1501; (b) Atilgan, S.; Ozdemir, T.; Akkaya, E. U. Org. Lett.
2008, 10, 4065e4067; (c) Yuan, M.; Li, Y.; Li, J.; Li, C.; Liu, X.; Lv, J.; Xu, J.; Liu, H.;
€
ꢁ
€
ꢁ
Wang, S.; Zhu, D. Org. Lett. 2007, 9, 2313e2316; (d) Baruah, M.; Qin, W.; Vallee,
R. A. L.; Beljonne, D.; Rohand, T.; Dehaen, W.; Boens, N. Org. Lett. 2005, 5,
4377e4380; (e) Qin, W.; Baruah, M.; Sliwa, M.; Van der Auweraer, M.; De
Borggraeve, W. M.; Beljonne, D.; Van Averbeke, B.; Boens, N. J. Phys. Chem. A
2008, 112, 6104e6114; (f) Coskun, A.; Akkaya, E. U. J. Am. Chem. Soc. 2005, 127,
10464e10465; (g) Guliyev, R.; Coskun, A.; Akkaya, E. U. J. Am. Chem. Soc. 2009,
131, 9007e9013; (h) Coskun, A.; Akkaya, E. U. J. Am. Chem. Soc. 2006, 128,
14474e14475.
9. (a) Qi, X.; Kim, S. K.; Han, S. J.; Xu, L.; Jee, A. Y.; Kim, H. N.; Lee, C.; Kim, Y.; Lee,
M.; Kim, S.-J.; Yoon, J. Tetrahedron Lett. 2008, 49, 261e264; (b) Qi, X.; Jun, E. J.;
Xu, L.; Kim, S.-J.; Hong, J. S. J.; Yoon, Y. J.; Yoon, J. J. Org. Chem. 2006, 71,
2881e2884.
d
¼2.87 (s, 12H), 3.82 (s, 3H), 5.86 (s, 2H), 5.90 (s, 2H), 6.81 (d,
J¼8.8 Hz, 2H), 6.99 (d, J¼7.7 Hz, 4H), 7.16 (dd, J¼7.3, 7.7 Hz, 4H),
7.31e7.40 (m, 6H), 7.76 (d, J¼7.7 Hz, 4H), 7.85 (d, J¼8.4 Hz, 2H), 8.32
10. Kowada, T.; Yamaguchi, S.; Ohe, K. Org. Lett. 2010, 12, 296e299.
11. (a) Sunahara, H.; Urano, Y.; Kojima, H.; Nagano, T. J. Am. Chem. Soc. 2007, 129,
5597e5604; (b) Gabe, Y.; Urano, Y.; Kikuchi, K.; Kojima, H.; Nagano, T. J. Am.
Chem. Soc. 2004, 126, 3357e3367; (c) Kennedy, D. P.; Kormos, C. M.; Burdette, S.
(d, J¼8.1 Hz, 2H). 13C NMR (75.5 MHz, CDCl3)
¼40.4, 52.1, 59.9,
d
106.7, 112.6, 117.7, 119.8, 121.3, 124.3, 125.2, 127.7, 127.8, 129.1, 130.2,
130.4, 134.4, 139.7, 139.9, 141.2, 142.3, 149.2, 152.0, 159.0, 160.6,
166.4. HRMS (FAB): calcd for C59H43O2N4F2B (Mþ), 888.3457. Found
888.3448.
ꢁ
C. J. Am. Chem. Soc. 2009, 131, 8578e8586; (d) Baruah, M.; Qin, W.; Basaric, N.;
De Borggraeve, W. M.; Boens, N. J. Org. Chem. 2005, 70, 4152e4157.
12. For recent reviews, see: (a) Alberico, D.; Scott, M. K.; Lautens, M. Chem. Rev. 2007,
107,174e238; (b) Satoh, T.; Miura, M. Chem. Lett. 2007, 36, 200e205; (c) Campeau,
L.-C.; Stuart, D. R.; Fagnou, K. Aldrichimica Acta 2007, 40, 35e41.
13. In our previous paper (Ref. 10), we used sodium hydroxide for a detosylation of
sp-FIP precursor and obtained sp-FIP in 99% yield. However, in the case of 4a
and 4b, the reaction systems were so complicated that the yields were 40% and
0%, respectively.
14. Valeur, B. Molecular Fluorescence; Wiley-VCH: Weinheim, Germany, 2002.
15. Sugiura, M.; Hirano, K. Biochem. Med. 1977, 17, 222e228.
16. Jensen, T.; Pedersen, H.; Bang-Andersen, B.; Madsen, R.; Jørgensen, M. Angew.
Chem., Int. Ed. 2008, 47, 888e890.
Acknowledgements
This work was financially supported by a Grant-in-Aid for Sci-
entific Research (B) (Grant No. 22350087) from the Japan Society
for the Promotion of Science (JSPS). T.K. gratefully acknowledges
the financial support by the Global COE Program ‘International