COMMUNICATION
Direct functionalization of BODIPY dyes by oxidative nucleophilic
hydrogen substitution at the 3- or 3,5-positionsw
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Volker Leen, Veronica Zaragozı Gonzalvo, Wim M. Deborggraeve, Noel Boens and
Wim Dehaen*
Received 24th March 2010, Accepted 14th May 2010
First published as an Advance Article on the web 8th June 2010
DOI: 10.1039/c0cc00568a
BODIPY dyes are shown to be susceptible to oxidative nucleo-
philic substitution of the a-hydrogens, incorporating nitrogen
and carbon nucleophiles in a single, high yielding step. The
reaction is an excellent alternative to conventional functionali-
zation of this popular fluorophore.
proceeded preferably in polar solvents. As for the oxidizing
agent, DDQ, CAN, or permanganate were able to effect the
reaction, but superior yields were obtained under oxygen
atmosphere in DMF.
Aliphatic amine nucleophiles where highly reactive under
the given conditions, and both primary (Table 1, entries 1–3)
and secondary (entry 4) amines readily participated in the
ONSH reactions. Due to the strong deactivation of the
BODIPY dye by the amine substituent, no disubstituted
product was formed. Aniline (entry 5) failed to substitute the
model compounds under the given conditions, and this was
presumably because of its lowered nucleophilicity.
The recent interest in direct functionalization rather than by
functional group interconversion has opened up a rapidly
expanding field of chemistry.1 Several approaches have been
developed to introduce functional groups, especially on aromatic
systems and through transition metal catalysis.2 As these
methods alleviate the need for tedious introduction of sub-
stituents and greatly improve synthetic power, this approach
will become increasingly important.
Carbon nucleophiles showed excellent reactivity. Indeed,
malonate addition resulted in the substituted ester 4e–f in
good yield (entries 6 and 7), and this under mildly basic
conditions. By increasing the amount of malonate and the
reaction time, the reaction goes to disubstituted 4g in excellent
yield (entry 8). Attesting to the generality of the reaction was
the rapid and clean incorporation of nucleophiles such as
enolates of ketones 4h and esters 4i (entries 9 and 10). All
the substitutions proceeded at room temperature, both for
amine and carbon nucleophiles. Heating only led to decreased
yields.
Application of such procedures to the popular boron
dipyrromethene (BODIPY) fluorophores3 is limited to palladium
and iridium catalyzed double bond introduction at the
2,6-positions.4 Up to now, no selective direct substitution of
hydrogen at the spectroscopically interesting 3,5-positions has
been reported. For derivatization of BODIPY dyes at these
positions, chlorinated derivatives have recently been shown to
be highly versatile.5 The ease of introduction of nucleophiles
via nucleophilic aromatic substitution (SNAr) has been
exploited in the synthesis, and subsequent functionalization,
of several halogenated BODIPY dyes.6
Conversely, oxygen and sulfur centred nucleophiles did not
lead to the formation of products. In the case of oxygen
nucleophiles, butanoxide or phenoxide (entries 11 and 12),
formation of substitution products could not be observed.
Substitution with sulfur nucleophiles, such as butanethiol or
thiophenol (entries 13 and 14), was very slow and resulted in
inseparable mixtures of mono and disubstituted products.
Prolonged reaction periods with excess of sulfur nucleophiles
In contrast with SNAr, the oxidative nucleophilic substitution
of hydrogen (ONSH) is less well-known.7 Generally, electron
poor aromatic systems are susceptible to equilibrated nucleo-
philic attack at activated positions, forming a sH-adduct.
Hydride does not act as a leaving group from this adduct,
but an oxidation step is needed to re-establish aromaticity. We
reasoned that the electron poor 3,5-positions of BODIPY dyes
1 could undergo this ONSH at the electron poor 3-carbon
(Scheme 1). The resulting negative charge on the sH-adduct 2
would be stabilized by the boron complex, and oxidation of
this intermediate could result in the substitution product.
Much to our delight we observed a reaction upon stirring a
meso-phenyl model BODIPY 1, in butylamine as the solvent,
under air. The yield was rather low, and from an optimization
of the reaction procedure (ESIw), it was clear that the reaction
Department of Chemistry, Katholieke Universiteit Leuven,
Celestijnenlaan 200f – bus 02404, 3001 Leuven, Belgium.
E-mail: wim.dehaen@chem.kuleuven.be; Fax: +32 16 327990;
Tel: +32 16 327439
w Electronic supplementary information (ESI) available: Experimental
procedures, characterisation data for the substrates and product. See
DOI: 10.1039/c0cc00568a
Scheme 1 Direct oxidative substitution on a BODIPY dye.
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This journal is The Royal Society of Chemistry 2010
4908 | Chem. Commun., 2010, 46, 4908–4910
Leen, Volker
