L. Li et al. / Bioorg. Med. Chem. Lett. 18 (2008) 3112–3116
3113
(i) NCS
Ar
Ar
THF, - 78 oC, 1.5 h
then 25 oC, 3 h
HN
conditions A or B
Ar
COOCH3
neat
H
N
cat. TFA
N
N
N
N
+
ArCHO
B
B
NH HN
34 %
25 oC, 1 h
(ii) DDQ
F2
F2
Cl
Cl
N
X
CH2Cl2, 25 oC, 1 h
MeO2C
Ar
Ar
3
BF3•OEt2, NEt3
A: MeCN, 25 °C, 10 min, gives 3a, 99 %, where X = Cl,
B: MeCN, reflux, 48 h, gives 3b, 93 %, where
N
HN
53 %
Scheme 1. Synthesis of the 3,5-dichloroBODIPY 1.
N
N
CH2Cl2, 25 oC, 24 h
B
F2
Cl
Cl
Cl
Cl
Ar =
X =
Br
N
CO2Me
1 98 %
Scheme 2. Mono- and bis-substitution on BODIPY 1.
(reactions of solubilized cyanide ions were less satisfac-
tory). The reaction of 1 in the presence of tin tetrachlo-
ride occurred selectively at the carbon to give compound
6a, but boron trifluoride promoted both types of dis-
placement reactions to give the tetracyanide 6b. Cyanide
has been used in SNAr reactions occurring at the meso
(or 8-position) of non-halogenated-BODIPY dyes,15–17
but this is the first time that either mode of reactivity
shown in Scheme 3 has been reported.
procedure made it possible to scale-up the syntheses to
5 g with minimal chromatography.
Displacement of the first of the two chlorines in 3,5-
dichloroBODIPY 1 with a piperidine derivative occurs
rapidly (Scheme 2). The second chlorine can be dis-
placed using extended reaction times at elevated temper-
atures. This particular piperidine derivative was of
interest because hydrolysis of the methyl ester would un-
mask two carboxylic acids that could be used for conju-
gation of this material to biomolecules.
The Lewis-acid-mediated conditions described above
were also applied to the aminated products 3. This led
to the corresponding B-dicyanated compounds
(Scheme 4).
7
The transformations shown in Scheme 2 were predict-
able for this substrate in combination with a soft nucle-
ophile. However, reactions of
1 with a harder
Table 1 shows photophysical data for molecules 1 and
3–7. Several trends can be observed using the starting
material 1 as a basis for comparison. Monoamination
and diamination cause red-shifts in the fluorescence, re-
duced quantum yields, and peak broadening. The
Stokes’ shift for 3a is high because the absorption max-
imum for this material is blue-shifted. The B-dimethylat-
ed compound 4 is spectroscopically similar to the parent
1 in all respects, and, just like 1 amination to give 5 blue-
shifts the absorption maximum. Replacement of the 3,5-
dichloro-substituents in 1 with cyanides gave the BF2
compound 6a and the B(CN)2-compound 6b. These
changes did not significantly affect the wavelengths for
the absorption or fluorescence maxima, but they did in-
crease the quantum yields by a factor of 4–5. Again,
monoamination and diamination caused red-shifts in
the fluorescence, peak broadening, and reduced quan-
tum yields.
nucleophile like methylmagnesium bromide could con-
ceivably occur at either of the electrophilic sites. It tran-
spired that displacement of the B-F bonds occurred
most rapidly, allowing relatively clean production of
the B-dimethylated compound 4. This could then be re-
acted with a piperidine derivative to give the SNAr prod-
uct 5.
Cyanide is a softer anion than methylmagnesium bro-
mide, but is harder than amines. The reaction of 3,5-
dichloroBODIPY 1 with this nucleophile reflects this
intermediate character. Displacement was achieved
using Lewis acidic activation of trimethylsilyl cyanide
Ar
B
Ar
MeMgBr
N
N
THF, 25 oC, 5 min
N
N
B
F2
Cl
Cl
Cl
Cl
Me Me
4 57 %
Ar
Ar
Lewis Acid A or B
Ar
B
+
TMSCN
HN
MeCN, 25 °C, 6 h
COOCH3
N
N
N
N
CH2Cl2, 25 oC, 2 h
B
B
F2
X2
Cl
Cl
NC
CN
Br
N
N
1
N
6
Me Me
Cl
A: SnCl4, gives 6a, 99 %, where X = F
B: BF3•OEt2, gives 6b, 71%, where X = CN
Ar =
H3COOC
Ar =
Br
5 50 %
Scheme 3. Syntheses of compound 6 having cyanide substituents.