β-formyl-BODIPYs from the Vilsmeier-Haack reaction

Article abstract of DOI:10.1021/jo901407h

(Chemical Equation Presented) A series of β-formyl-BODIPYs 2 were synthesized in high yields from tetramethyl-BODIPYs 1 via the Vilsmeier-Haack reaction and were further functionalized using a Knoevenagel condensation to generate novel BODIPYs 3 and 4. 20

Full text of DOI:10.1021/jo901407h

pubs.acs.org/joc
structures. Consequently, these molecules have found wide
β-Formyl-BODIPYs from the Vilsmeier-Haack
Reaction
applications as fluorescent labels for DNA3 and proteins4
and have attracted renewed research interests2 in highly diverse
fields as labeling reagents,3-5 fluorescent switches,6 chemosen-
sors,7,8 laser dyes,9 photosensitizers,10 energy transfer cas-
settes,11 supramolecular fluorescent gels,12 and harvesting
arrays.13 Currently, their further application is hampered by
the limited availability associated with synthetic limitations,
especially for those compounds with extended conjugation.
BODIPY itself is intrinsically electron-rich and has several
positions available for functional modification, but most of
the functionalization methods are not straightforward.2
Among these, functionalization at the 8-(meso) position
(Figure 1) is relatively easy compared with the pyrrolic
positions via the condensation of various aryl aldehydes
(Lindsey’s method)14a or acyl chlorides with pyrroles;14
many functional groups such as ligands or biomolecules
are often introduced via this method. However, the meso
substituents and the BODIPY chromophore are almost
perpendicular to each other, resulting in poor electronic
conjugation between the two moieties. Thus, functionaliza-
tion at the pyrrolic positions is more desirable.2,15 Typical
approaches include (1) de novo syntheses from appropriately
substituted pyrroles if accessible and (2) the direct introduc-
tion of pyrrolic substituents to a ready-made partially un-
substituted BODIPY chromophore;2 this latter method is
efficient, and substitution can be performed at both R- and
β-positions of the chromophore (Figure 1). Methods avail-
able for functionalization at the R-position include Knoeve-
nagel condensations of 3,5-dimethyl-BODIPYs using aryl
aldehyde,16 nucleophilic substitutions,17a,b or organometallic
couplings18 of 3,5-dichloro-BODIPYs17a,b and analogues.17c
Lijuan Jiao,* Changjiang Yu, Jilong Li, Zhaoyun Wang,
Min Wu, and Erhong Hao
Anhui Key Laboratory of Functional Molecular Solids,
College of Chemistry and Material Science, and Anhui Key
Laboratory of Molecular Based Materials, Anhui Normal
University, Wuhu 241000, China
jiao421@mail.ahnu.edu.cn
Received July 2, 2009
A series of β-formyl-BODIPYs 2 were synthesized in high
yields from tetramethyl-BODIPYs 1 via the Vilsmeier-
Haack reaction and were further functionalized using a
Knoevenagel condensation to generate novel BODIPYs
3 and 4.
Boradiazaindacenes, known as BODIPY dyes, are
strongly UV-absorbing small molecules with high fluores-
cence quantum yields, sharp fluorescence emissions, high
photophysical stability, and low sensitivity to the polarity
and pH of their environment.1,2 Their fluorescence profiles
can be easily tuned by way of small modifications to the
(9) (a) Arbeloa, T. L.; Arbeloa, F. L.; Arbeloa, I. L.; Garcia-Moreno, I.;
Costela, A.; Sastre, R.; Amat-Guerri, F. Chem. Phys. Lett. 1999, 299, 315. (b)
Mula, S.; Ray, A. K.; Banerjee, M.; Chaudhuri, T.; Dasgupta, K.;
Chattopadhyay, S. J. Org. Chem. 2008, 73, 2146.
(10) Yogo, T.; Urano, Y.; Ishitsuka, Y.; Maniwa, F.; Nagano, T. J. Am.
Chem. Soc. 2005, 127, 12162.
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DOI: 10.1021/jo901407h
r
Published on Web 09/01/2009
J. Org. Chem. 2009, 74, 7525–7528 7525
2009 American Chemical Society

Jiao et al.
JOCNote
SCHEME 1. Syntheses of BODIPYs 2
Knoevenagel condensation as shown in Scheme 2 to demons-
trate the ready transformation of these β-formyl-BODIPYs.
The formylation procedure was extended to aza-BODIPY 5
as shown in Scheme 3 to exemplify the versatility of this
reaction.
FIGURE 1. IUPAC numbering system for BODIPY and the most
susceptible positions on tetramethyl-BODIPY for electrophilic
substitution reactions.2a
BODIPYs 1a-f were chosen because they were easily
available via Lindsey’s method14a from the condensation of
2,4-dimethylpyrrole with the corresponding aryl aldehydes.
2,4-Dimethylpyrrole was chosen to limit possible reaction
positions for the formylation reaction and to thus avoid
the generation of complex mixtures. The standard
Vilsmeier-Haack reaction required stoichiometric amounts
of Vilsmeier reagent prepared via interaction between POCl3
and DMF for 1 h at room temperature. Initially, a standard
condition was used for the formylation of BODIPY 1a in
DCM at room temperature, but no reaction occurred over 1
week. Simply raising the temperature to refluxing or increas-
ing the Vilsmeier reagent to an excess amount (up to 200
equiv) made no difference. With the combination of these
two factors, BODPY 2a was generated slowly and in low
yield, and most of the starting BODIPY 1a was recovered.
Influenced by the formylation conditions used for the por-
phyrin system, in which the refluxing 1,2-dichloroethane is
generally used as solvent, the formylation of BODIPY 1a
was also carried out in refluxing 1,2-dichloroethane instead
of DCM. In this case, in the presence of an excess amount
of Vilsmeier reagent, BODIPY 1a was completed consumed
within 2 h. After hydrolysis of the intermediate imin-
ium salts, followed by the usual workup and column chro-
matographic isolation, BODIPY 2a was obtained in 89%
yield.
BODIPYs 1b-f exhibited similar reactivity under the
same reaction conditions as shown in Scheme 1 and are also
completely consumed within 2 h. After workup and column
chromatographic isolation, BODIPYs 2b-f were obtained
in 87-93% yields, as summarized in Table 1. The 1H NMR
spectra give a typical singlet one-proton signal between 9.99
and 10.03 ppm for the formyl protons for most of the
β-formyl-BODIPYs, with the exception of 2e, which has
the appropriate signal at 9.80 ppm. Crystals of BODIPY 2c
suitable for X-ray analysis were obtained via slow evapora-
tion of a DCM solution. It has a planar BODIPY framework
as shown in Figure 2. The dihedral angle between the phenyl
and the BODIPY core is 60°, which is different from the 78°
dihedral angle reported in BODIPY 1d.29 The plane defined
by the F-B-F atoms is perpendicular to that of the BOD-
IPY core, similar to previous reported results.29,30
In the mesomeric structures2a of BODIPY as shown in Figure 1,
the 2,6-(β-)positions of the BODIPY core bear the least positive
charge and should be most susceptible to electrophilic attack.
Surprisingly, only limited electrophilic reactions have been
reported at these positions, including (1) halogenation,10 (2)
sulfonation,19 (3) nitration,20 and (4) palladium-catalyzed
C-H functionalization.21 There are no reports of common
electrophilic substitution reactions such as the Vilsmeier-
Haack reaction.
The Vilsmeier-Haack reaction of pyrroles22 using DMF/
POCl3 has been extended to thiophenes,23 indoles,24 bipyr-
roles,25 porphyrins,26 chlorins,26 and dipyrromethanes27 and
represents highly efficient approaches to the introduction of
various substituents into specific positions of these mole-
cules. For example, formylporphyrins, in general, and
β-formylporphyrins, in particular, are valuable precursors
in the synthesis of porphyrin derivatives with important
applications in biomedical and natural sciences.28 The in-
troduction of formyl groups into a BODIPY core is an
important method for the further elaboration of BODIPYs.
We wondered if the same strategy could be used for the
particular case of BODIPYs to generate the desired
β-formyl-BODIPYs.
Herein we report in detail the syntheses of a series of
β-formyl-BODIPYs 2 via the Vilsmeier-Haack reaction on
BODIPYs 1 as shown in Scheme 1 and their photophysical
properties. BODIPY 2a was further functionalized using a
(19) Li, L.; Han, J.; Nguyen, B.; Burgess, K. J. Org. Chem. 2008, 73, 1963.
(20) Shah, M.; Thangaraj, K.; Soong, M.-L.; Wolford, L. T.; Boyer, J. H.;
Politzer, I. R.; Pavlopoulos, T. G. Heteroat. Chem 1993, 4, 39.
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(b) Ptaszek, M.; McDowell, B. E.; Lindsey, J. S. J. Org. Chem. 2006, 71, 4328.
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Compd. 1980, 16, 230.
(24) Chatterjee, A.; Biswas, K. M. J. Org. Chem. 1973, 38, 4002.
(25) Vogel, E.; Kocher, M.; Schmickler, H.; Lex, J. Angew. Chem., Int. Ed.
1986, 25, 257.
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Silva, A. M. G.; Tome, A. C.; Neves, M. G. P. M. S.; Silva, A. M. S.;
Cavaleiro, J. A. S. J. Org. Chem. 2002, 67, 726.
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Fisher, A. J.; Smith, K. M. Angew. Chem., Int. Ed. 1997, 36, 2497. (b)
Wickramsinghe, A.; Jaquinod, L.; Nurco, D. J.; Smith, K. M.Tetrahedron 2001,
57, 4261. (c) Tamaru, S. I.; Yu, L. H.; Youngblood, J. W.; Muthukumaran, K.;
Taniguchi, M.; Lindsey, J. S. J. Org. Chem. 2004, 69, 765. (d) Laha, J. K.;
Dhanalekshmi, S.; Taniguchi, M.; Ambroise, A.; Lindsey, J. S. Org. Process
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Chem. 2000, 65, 543. (b) Shanmugathasan, S.; Edwards, C.; Boyle, R. W.
Tetrahedron 2000, 56, 1025.
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1997, 36, 1333.
7526 J. Org. Chem. Vol. 74, No. 19, 2009

Jiao et al.
JOCNote
TABLE 1. Isolated Yields and Characteristic 1H NMR Signals for
BODIPY 2a-f from Mono-β-formylation of the Corresponding BODIPY
1a-f
FIGURE 3. Perspective view of compound 3, including atom
numbering.
X-ray analysis were obtained via slow evaporation of a DCM
solution. BODIPY 3 has a planar BODIPY framework as
shown in Figure 3. The dihedral angle between the phenyl
and the BODIPY core is 60°, similar to that of BODIPY 2c.
The plane defined by the F-B-F atoms is also almost
perpendicular with that of the BODIPY skeleton with a
dihedral angle of about 82°, which is only slightly different
from that of BODIPY 2c. Thus, BODIPY 3 shows only a
small distortion of the structure compared with that of
β-formyl-BODIPY 2a.
With several new BODIPYs in hand, we further studied
the photophysical properties of these compounds. BODIPYs
1-3 are colorful to the eye, and most of them are brilliant
upon irradiation. Similar to the starting BODIPYs 1, these
new BODIPYs gave good dispersion of UV absorbance and
fluorescence emission and were insensitive to the polarity of
the media as exemplified for BODIPY 2a in Figure S1 in the
Supporting Information. Their spectral data in DCM are
compared with those of the starting BODIPYs 1 in Table 2.
The molar absorptivities of BODIPYs 2 are comparable to
those of BODIPYs 1. There are small blue-shifts (2-6 nm) of
the absorption and emission bands for BODIPYs 2, with the
exception of BODIPY 2f in which a relatively larger (14 nm)
blue-shifted band is observed. Most of BODIPYs 2 have good
fluorescence quantum yields, with the exception of BODIPYs
1d and 2d. This is attributed to the strong electron-withdrawing
effect of the nitro-substituted benzene moiety at the 8-position,
which leads to photoinduced electron-transfer processes and
reduces the fluorescence quantum yield as described in the
literature.31 With the increased conjugation on BODIPY 3, the
spectra become slightly broader and are red-shifted (20 nm for
absorption and 27 nm for fluorescence emission) compared
with those of BODIPY 2a.
FIGURE 2. Perspective view of compound 2c, including atom
numbering.
SCHEME 2. Synthesis of BODIPY 3 and 4
By further extending the reaction time, a mixture of mono-
and diformylated BODIPYs was obtained according to TLC
monitoring. The diformylated BODIPYs failed to survive
the subsequent hydrolysis conditions and led to unidentified
polar complex mixtures. Variation of the hydrolysis condi-
tions, such as changing the base, lowering the temperature,
and performing under argon, gave similar results, and no
diformylated BODIPYs were isolated.
With the efficient generation of β-formyl-BODIPYs 2 in
high yields, and to demonstrate the easy structural modifica-
tion of these β-formyl-BODIPYs, BODIPY 2a was further
functionalized via Knoevenagel condensations with malo-
nonitrile or methyl acetoacetate as shown in Scheme 2. After
column separation, BODIPY 3 was obtained in 80% yield,
while BODIPY 4 was obtained in lower yield as a mixture of
two regioisomers (1.3:1). Crystals of BODIPY 3 suitable for
To test the versatility of this formylation reaction, we
further extended the reaction procedure to aza-BODIPY 532
as shown in Scheme 3, from which β-formylaza-BODIPY 6
was obtained in 74% yield. The resulting BODIPY 6 shows a
good fluorescence quantum yield and has blue-shifted ab-
sorption (22 nm) and emission (17 nm) bands compared with
those of the starting BODIPY 5, as shown in Table 2. Aza-
BODIPYs generally have long-wavelength absorption and
(31) (a) Tanaka, K.; Miura, T.; Umezawa, N.; Gunnlaugsson, T.; Kikuchi,
K.; Higuchi, T.; Nagano, T. J. Am. Chem. Soc. 2001, 123, 2530. (b) Ueno, T.;
Urano, Y.; Setsukinai, K.; Takakusa, H.; Kojima, H.; Kikuchi, K.; Ohkubo, K.;
Fukuzumi, S.; Nagano, T. J.Am. Chem.Soc. 2004, 126, 14079.(c)Sunahara, H.;
Urano, Y.; Kojima, H.; Nagano, T. J. Am. Chem. Soc. 2007, 129, 5579.
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O’Shea, D. F. J. Am. Chem. Soc. 2004, 126, 10619.
J. Org. Chem. Vol. 74, No. 19, 2009 7527

Jiao et al.
JOCNote
1
TABLE 2. Photophysical Properties of BODIPY 1a-f, 2a-f, 3, 5, and
6 in DCM
a reddish-brown powder: mp > 300 °C; H NMR (300 MHz,
CDCl3) δ 10.00 (s, 1H), 7.53 (s, 3H), 7.29 (s, 2H), 6.15 (s, 1H),
2.83 (s, 3H), 2.62 (s, 3H), 1.65 (s, 3H), 1.42 (s, 3H); 13C NMR
(75 MHz, CDCl3) δ 186.0, 161.7, 156.5, 147.4, 143.6, 142.9,
134.1, 129.6, 129.5, 127.7, 126.3, 124.1, 15.1, 14.9, 13.0, 11.6;
ESI-MS 351.2 [M - H]-, 374.4 [M þ Na] þ. Anal. Calcd for
C20H19BF2N2O: C, 68.21; H, 5.44; N, 7.95. Found: C, 68.34, H
5.51, N 7.12.
BODIPY 3. To a mixture of 2a (130 mg, 0.4 mmol) and
malononitrile (106 mg, 1.6 mmol) in toluene (20 mL) were added
one drop of piperidine and a catalytic amount of HOAc under
argon. The reaction mixture was stirred at refluxing conditions
under argon for 10 h and then washed with water (2 ꢀ 50 mL).
The organic layers were combined, dried over anhydrous
MgSO4, and evaporated in vacuo. The crude product was
purified using column chromatography (silica gel, DCM) to
give BODIPY 3 (128 mg, 80%) as an orange powder: mp 213-
216 °C; 1H NMR (300 MHz, CDCl3) δ 7.69 (s, 1H), 7.53-7.55
(m, 3H), 7.26-7.29 (m, 2H), 6.18 (s, 1H), 2.63 (s, 3H), 2.61 (s,
3H), 1.43 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 163.1, 153.5,
152.6, 148.2, 142.8, 139.1, 134.5, 133.7, 130.9, 129.7, 127.6,
124.7, 123.0, 114.4, 113.2, 81.9, 15.2, 14.9, 14.3, 14.2; ESI-MS
399.2 [M - H]-. Anal. Calcd for C23H19BF2N4: C, 69.02; H,
4.78; N, 14.00. Found: C, 68.89, H 4.68, N 14.21.
BODIPY
λmax (nm) log (εmax
)
λf (nm) Stokes shift (nm)
Φf
1a
2a
1b
2b
1c
2c
1d
2d
1e
2e
1f
2f
3
500
494
502
498
500
494
504
500
500
496
510
496
514
646
624
5.02
4.81
4.77
4.79
4.92
4.70
4.94
4.77
4.64
4.81
4.74
4.81
4.74
4.90
4.73
520
516
522
519
519
516
527
528
520
518
532
518
543
680
663
20
22
20
21
19
22
23
28
20
22
22
22
29
34
39
0.36
0.41
0.29
0.37
0.38
0.40
<0.01
0.08
0.46
0.64
0.51
0.51
0.45
0.34
0.45
5
6
SCHEME 3. Synthesis of Aza-BODIPY 6
Aza-BODIPY 6. A mixture of DMF (3 mL) and POCl3
(3 mL) was stirred in an ice bath for 5 min under argon. After
being warmed to room temperature, it was stirred for an
additional 30 min. To this reaction mixture was added BODIPY
532 (90 mg, 0.18 mmol) in dichloroethane (6 mL); the mixture
was raised to 70 °C and stirred for an additional 20 h. The
mixture was then cooled to room temperature and slowly
poured into saturated aqueous NaHCO3 (200 mL) under ice-
cold conditions. After being warmed to room temperature, the
mixture was stirred for 1 h. The organic layers were combined,
dried over anhydrous MgSO4, and evaporated in vacuo. The
crude product was further purified using column chromato-
graphy (silica gel, hexane/CH2Cl2 = 3:2, v/v) to give BODIPY 6
(70 mg, 74%) as a dark blue greenish powder: mp > 300 °C;
1H NMR (300 MHz, CDCl3) δ 9.70 (s, 1H), 7.99 (d, J = 7.4 Hz,
4H), 7.79 (d, J = 7.0 Hz, 2H), 7.66 (d, J = 4.2 Hz, 2 H),
7.44-7.33 (m, 12 H), 7.13 (s, 1H); 13C (75 MHz, CDCl3) δ 186.2,
166.3, 159.3, 148.8, 147.5, 143.2, 142.1, 132.7, 132.0, 130.9,
130.8, 130.7, 130.3, 130.21, 130.16, 129.8, 129.7, 129.6, 128.9,
128.8, 128.6, 128.0, 127.8, 126.1, 121.5; ESI-MS 526.2 [M þ H]þ.
Anal. Calcd for C33H22BF2N3O: C, 75.44; H, 4.22; N, 8.00.
Found: C, 75.65, H, 4.18, N 8.24.
emission properties but suffer from limited potential for their
synthetic modification because functionalization at the
8-position is not possible. Thus, our formylation reaction
provided a useful approach for the efficient modification of
aza-BODIPYs.
In summary, modified Vilsmeier-Haack reactions using
excess amounts of DMF/POCl3 in refluxing 1,2-dichloro-
ethane have been successfully applied for the formylation of
the BODIPY core at its β-position, from which a series of
BODIPYs 2 have been obtained in high yields. The further
functionalization of 2a via the Knoevenagel condensation
generates novel BODIPYs 3 and 4 with extended conjuga-
tion. The formylation procedure was further extended to
aza-BODIPY 5 and smoothly produced β-formylaza-BOD-
IPY 6 in good yield.
Experimental Section
BODIPY 2a. A mixture of DMF (6 mL) and POCl3 (6 mL)
was stirred in an ice bath for 5 min under argon. After being
warmed to room temperature, it was stirred for additional 30
min. To this reaction mixture was added 1a (158 mg, 0.5 mmol)
in dichloroethane (60 mL), the temperature was raised to 50 °C,
and the mixture was stirred for an additional 2 h. The reaction
mixture was cooled to room temperature and slowly poured into
saturated aqueous NaHCO3 (200 mL) under ice-cold condi-
tions. After being warmed to room temperature, the reaction
mixture was further stirred for 30 min and washed with water
(2 ꢀ 150 mL). The organic layers were combined, dried over
anhydrous MgSO4, and evaporated in vacuo. The crude product
was further purified using column chromatography (silica gel,
EtOAc/hexane = 1:4, v/v) to give BODIPY 2a (157 mg, 89%) as
Acknowledgment. This work is supported by the National
Nature Science Foundation of China (Grant Nos. 20802002
and 20772001), Anhui Provincial Natural Science Founda-
tion (Grant No. 090416221), and the Educational Commis-
sion of Anhui Province (Grant No. KJ2009A130).
Supporting Information Available: General experimental
methods, experimental procedures, compound characterization
data and copies of 1H and 13C NMR spectra for all new
compounds, crystallographic information files (CIFs) for com-
pound 2c and 3, and UV-vis and fluorescence spectra for all
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
7528 J. Org. Chem. Vol. 74, No. 19, 2009