Job/Unit: O31900 /KAP1 Date: 11-02-14 18:44:28 Pages: 8 FULL PAPER DOI: 10.1002/ejoc.201301900 High Yield S N Ar on 8-Halogenophenyl-BODIPY with Cyclic and Acyclic Polyamines Yulia Volkova, [a] Bertrand Brizet, [a,b] Pierre D. Harvey, [b] Franck Denat,* [a] and Christine Goze* [a] Keywords: Dyes/pigments / Fluorescence / Medium-ring compounds / Nucleophilic substitution Selective nucleophilic aromatic substitutions with several polyamines were performed in very good yields on halogeno- Introduction In the immense library of fluorophores, 4,4-difluoro-4- bora-3a,4a-diaza-s-indacene (BODIPY) derivatives are of the highest interest due to their remarkable photophysical properties. [1] Indeed, this class of fluorescent dyes exhibit high molar absorption coefficients, ε (λ), and fluorescence quantum yields, Φ F , narrow emission bandwidths with high peak intensities, emission wavelengths in the visible spectral region, and fluorescence lifetimes, τ F , in the nanosecond range. Additionally, they present good stability towards light irradiation and various chemicals, good solubility in most organic solvents, and very low self-aggregation in solution. Moreover, their spectroscopic and photophysical properties can be fine-tuned with ancillary substituent groups at the appropriate positions of the difluoroboron dipyrromethene core. Notably, the introduction of a specific chelate on the meso-phenyl-substituted BODIPY via a ni- trogen atom allows for the formation of very selective fluo- rescent sensors based on BODIPY derivatives. [2] So far, only a few routes have been exploited to introduce func- tional groups on 8-halogenophenyl-BODIPY. These reac- tions overwhelmingly involve cross-couplings such as Suzuki, [3] and Sonogashira–Hagihara reactions. [4] We recently reported the design and properties of some BODIPY-polyazamacrocycles that found applications in areas such as cation sensing [6] and molecular imaging. [7] Notably, for cation sensing, the macrocycles were intro- duced through S N Ar nucleophilic substitutions at one N atom of the polyazamacrocycle in the 3-chlorosubstituted [a] Institut de Chimie Moléculaire de l’Université de Bourgogne (ICMUB) 9, 9, avenue Alain Savary, 21000 Dijon, France E-mail: franck.denat@u-bourgogne.fr christine.goze@u-bourgogne.fr http://www.icmub.fr [b] Département de Chimie, Université de Sherbrooke, Sherbrooke, Québec, J1K 2R1, Canada Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/ejoc.201301900. Eur. J. Org. Chem. 0000, 0–0 © 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 1 phenyl BODIPY derivatives containing an activating nitro group. position of BODIPY. [8] However, the incorporation of dif- ferent nucleophiles through nucleophilic aromatic substitu- tion reactions (S N Ar) has been neglected, despite the poten- tial of this simple catalyst-free reaction. [5] This approach has the unfortunate downfall that the 3- and 5-positions of the resulting BODIPY derivatives are no longer available for further functionalization after the first substitution. Alternatively, reaction at the meso-position of the BODIPY compounds could be exploited, which should allow the introduction of different macrocycles, while pre- serving the 3- and 5-positions. We now report a series of efficient S N Ar nucleophilic substitution reactions of 8-halogenophenyl-BODIPY deriv- atives with different polyamines and polyazamacrocycles. A NO 2 group was placed at the ortho-position relative to the carbon atom bearing the halogen to enhance the electrophi- licity of the latter. The substitution can hence be performed in very high yield under mild conditions while preserving the methyl groups intact on the pyrrole rings for further orthogonal reactions such as Knoevenagel condensations. [9] Moreover, the NO 2 group can also be conveniently reduced to NH 2 for exploitation in additional transformations. This simple and efficient multifunctionalization of BODIPY is expected be extended to other nucleophiles, such as thiols. [5] This approach using orthogonal reactions is very conve- nient for materials design as well as biological applications. Results and Discussion Although the boron acid center is sensitive to Grignard reagents, acetylide anions, and alkoxydes, it is less reactive than electron-poor aromatics. [5] Indeed, the reactivity of the halogeno-aromatic function towards S N Ar reactions with a variety of polyamine groups was studied (Scheme 1). Inter- estingly, when an excess of acyclic polyamines (4 equiv.) were added to precursor 1 (3-nitro-4-fluorophenyl- BODIPY), [10] monosubstituted compounds could be easily obtained in very high yield (Table 1).