dipyrromethenes and their substitution via SNAr yielding
heteroatom (N, O, S) meso-substituted derivatives and by
palladium-catalyzed Suzuki, Stille, and Sonogashira cross-
coupling.
Scheme 1. Synthesis of 8-Halogenated BODIPY Dyes
Our proposed synthesis, outlined in Scheme 1, intro-
duces the halogen through deoxygenative substitution on
a dipyrrylketone. An early mention of this reaction dates
back to the work of Fisher and Ort, where a chlorinated
dipyrrin was obtained by the action of phosgene.8 Because
we wanted to avoid this highly toxic gas, other synthetic
routes toward halogenated dipyrrins were investigated.
Following literature procedures,9 the oxidative conver-
sion of dipyrrylthioketone to symmetric ketone 1 using
hydrogen peroxide is efficient and fast, and product 1 is
isolated as a crystalline solid. Initial attempts to bring
about halogenation of ketone 1 used phosphorus oxy-
chloride and showed rapid conversion to the dipyrrinium
salt. In situ deprotonation and complexation subsequently
resulted in a single fluorescent compound, which was
identified as the target meso-chlorinated compound 2a.
Similarly, phosphorus oxybromide converted di(pyrrol-2-
yl)methanone 1 to a meso-brominated dipyrrinium salt,
which was deprotonated and complexed in situ to yield 2b.
Additional efforts to screen for other halogenating agents,
suchasSOCl2, PCl3, and PCl5, all resultedinlowered yields
and significant side product formation. The use of PI3 as
iodinating agent was unsuccessful. The resulting mixture
was contaminated with several byproducts, and a good
yield of the desired borondiaza-s-indacene could not be
attained. All attempts at fluorination led to a complex
reaction mixture.
However, halogen exchange could be achieved by stir-
ring chlorinated 2a in acetone in the presence of sodium
iodide. In this modified Finkelstein procedure, insoluble
sodium chloride precipitates and drives the reaction to the
meso-iodinated dye 2c, which is isolated in good yield.
In the direct conversion of the ketone to sulfonates,
by reaction with trifluoromethyl or nonaflyl sulfonyl
anhydride, the yellow color of a dipyrrin intermediate is
observed, but complexation with boron trifluoride did not
result in the formation of the boron heterocycle.
Despite early worries about the stability of such halo-
genated compounds, compounds 2 proved to be stable at
room temperature as highly crystalline solids.
8-HaloBODIPYs are interesting compounds because
they are very promising starting materials for the prepara-
tion of more complex meso-substituted BODIPY analo-
gues via elaboration on the reactive halogen through,
e.g., SNAr or transition-metal-catalyzed transformations
(Suzuki, Stille, Heck, Negishi, Sonogashira, etc.).
Similarly, 8-substituted ethers can be obtained by nucleo-
philic displacement of the halogen substituent. As such,
aryl (3d) and alkyl (3e) ethers were obtained by reaction
of 2a and phenol or methanol under basic conditions
(Scheme 2).
Scheme 2. Nucleophilic Displacement of Chlorine on Dye 2a
Transition-metal-catalyzed cross-couplingof8-haloBO-
DIPYswitharylboronicacids isanalternate strategytothe
classic condensationꢀoxidation sequence of pyrroles and
aromatic aldehydes.2 Thus, standard Suzuki (Table 1,
entries 1ꢀ4) and Stille (Table 1, entry 5 and 6) cross-
coupling procedures efficiently led to the substituted dyes
4a and 4b (Table 1). Heteroaromatic groups can also be
introduced, as exemplified by the formation of 8-(2-
thienyl)BODIPY 4c (Table 1, entry 6), which is a potential
building block for the preparation of novel luminescent
materials.5a Beneficially, our method eliminates the need
for Cuþ reagents, which are required in the Liebeskindꢀ
Srogl cross-coupling of 8-methylthioBODIPYs with boronic
acids.5 All halogenated (Cl, Br, I) compounds 2 undergo the
Suzuki and Stille reactions with varying yields.
Sonogashira cross-coupling with phenylacetylene with
the iodinated dye 2c led to complex reaction mixtures in
which the desired product could only be observed in trace
amounts. The side reactions and decomposition could be
circumvented by shifting to the chlorinated dye 2a, which
reacted veryrapidly at low temperatures (30 min at 0 °C) to
provide alkyne 4d in good yield (Table 1, entry 7). Such
alkynes with bathochromically shifted spectra are interest-
ing for the development of new sensors and fluorescent
materials, but their synthesis has previously only been
reported from unstable propynoyl chloride.10
The chloride substituent is an efficient leaving group
in SNAr reactions. 8-ChloroBODIPY 2a can be used to
prepare the previously reported amine 3a4 and thioether
fluorophores 3b and 3c,4 which are isolated in high yield
after stirring with the suitable nucleophile and a base.
Expansion of the methodology to substituted pyrroles
and the corresponding dipyrrylketones, such as 5, led to
the synthesis of both symmetrically and asymmetrically
(7) De Meijere, A., Diederich, F. Metal-Catalyzed Cross-Coupling
Reactions, 2nd ed.; Wiley-VCH: Weinheim, 2004.
(8) Fisher, H.; Ort, H. Liebigs Ann. Chem. 1933, 502, 237.
(9) Plater, M. J.; Aiken, S.; Bourhill, G. Tetrahedron 2002, 58, 2405.
(10) Bonardi, L.; Ulrich, G.; Ziessel, R. Org. Lett. 2008, 10, 2183.
Org. Lett., Vol. XX, No. XX, XXXX
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Leen, Volker
