Efficient deprotection of F-BODIPY derivatives: removal of BF2 using Brønsted acids

Summary The effective and efficient removal of the BF2 moiety from F-BODIPY derivatives has been achieved using two common Brønsted acids; treatment with trifluoroacetic acid (TFA) or methanolic hydrogen chloride (HCl) followed by work-up with Ambersep® 900 resin (hydroxide form) effects this conversion in near-quantitative yields. Compared to existing methods, these conditions are relatively mild and operationally simple, requiring only reaction at room temperature for six hours (TFA) or overnight (HCl).

Related efforts have wrought substitution at boron in F-BODIPY analogues without removing it from the dipyrrin.For example, Lundrigan et al. have effected direct conversion of F-BODIPYs to Cl-BODIPYs using boron trichloride [20], while Jiang et al. achieved substitution of fluoride by acetate using trimethylsilyl chloride followed by acetic acid [21].
Herein we report the effective and efficient removal of the BF 2 moiety from F-BODIPY derivatives using two common Brønsted acids: treatment with trifluoroacetic acid (TFA) or methanolic hydrogen chloride (HCl) at room temperature followed by work-up with Ambersep ® 900 resin (hydroxide form) achieves this conversion in near-quantitative yields.
Preparation of nitro-F-BODIPY 8 was initially attempted by adapting the reported synthetic method [10].However the ethe- real complex 8•Et 2 O was isolated by flash column chromatography, rather than 8 itself (readily evident in the 1 H and 13 C NMR spectra).To the best of our knowledge, the complexation of Et 2 O in this way has not been reported in previous syntheses of F-BODIPY derivatives.Considering that the same procedures were used to synthesize and purify 8 as we used to prepare 11 free from Et 2 O (vide infra), and given previous reports on the ability of nitrogen oxides (e.g., NO, N 2 O 3 and N 2 O 4 ) to complex with boron trifluoride [26][27][28][29], the nitro group is presumably the key factor in the complexation of 8 with Et 2 O. Washing with aqueous and organic solvents did not completely remove the complexed ether, but uncomplexed 8 was obtained after recrystallization from ethyl acetate.The structure of this F-BODIPY derivative was determined by NMR and X-ray crystallography (Figure 1), and its purity confirmed by elemental analysis.Conversion of the nitro compound 8 to the corresponding azide 9 was achieved by palladium-catalyzed reduction [10] followed by diazotization of the amine and subsequent substitution with azide [30].4-Bromobenzaldehyde (7) was readily converted to ethynyl-F-BODIPY 11 according to the literature procedures [11,31].Azido-F-BODIPY 9 and ethynyl-F-BODIPY 11 were reacted respectively with the complementary propargyl-tri-Boc cyclam 12 [23,32] and 2-azidoethyl-tri-Boc cyclam 13 [24,25] under the modified click conditions we have reported previously [24] to generate the Boc-protected triazolyl-cyclam/F-BODIPY conjugates 3 and 4 in excellent yields.
In attempting to remove the Boc groups from 3 and 4, we have discovered a facile method for the removal of BF 2 from these F-BODIPY derivatives using Brønsted acids (Scheme 3, Table 1) (see Supporting Information File 1 for experimental data).Thus 3 was converted efficiently to 14 (96-99% yield) with the loss of three Boc groups and the BF 2 moiety, using either a mixture of TFA/DCM/H 2 O (90:5:5) or a methanolic solution of hydrogen chloride (2.8 M) at room temperature, followed by basification with a suspension of excess Ambersep ® 900 resin (hydroxide form) in methanol.Similarly, 4 afforded 15 (96-98% yield) under the same reaction conditions.
In an initial investigation of the scope of this transformation, each of the F-BODIPY derivatives prepared in this study was subjected to the reaction conditions that rendered BF 2 -removal from 3 and 4 (Scheme 3, Table 1).Nitro-F-BODIPY 8 was readily converted to dipyrrin 16 by the TFA method in quantitative yield (100%).With this substrate, the HCl method required an extended reaction time (48 hours) to give 16 in excellent yield (92%).Near-quantitative (99%) conversion of azido-F-BODIPY 9 to dipyrrin 17 was achieved using both methods.Ethynyl-F-BODIPY 11 was successfully converted to dipyrrin 18 using both Brønsted acids: LC-MS analysis (see Supporting Information File 1) revealed the desired 18 as the major product at m/z 301.2, however, the crude product also contained a minor contaminant at m/z 319.3, consistent with addition of water to the alkyne. 1  this impurity was present at ≤5% abundance, but HPLC purification was required to generate analytically pure 18 which compromised the final yields (53% for both methods).

H NMR analysis indicated that
We are aware of two previous reports investigating the treatment of BODIPYs with Brønsted acids.Yang et al. used 11 B NMR to monitor the stability of BODIPYs in the presence of di-or trichloroacetic acid, reporting 'partial decomposition' of an F-BODIPY derivative without characterizing the breakdown product(s) [33].While Liras et al. reported the synthesis of a single aminodipyrrin product from the corresponding 3-amino-and 3-acetamido-F-BODIPY precursors, using 'HClcatalyzed deacetylation conditions' (HCl in ethanol) to effect both deacetylation and deboration [34].

Conclusion
In conclusion, we have serendipitously achieved efficient removal of the BF 2 moiety from F-BODIPY derivatives using either the organic acid TFA or the inorganic acid HCl.These conditions are complementary to those previously reported for converting F-BODIPYs to the parent dipyrrins using either strong bases or Lewis acids.Compared to existing methods, the Brønsted acid conditions are relatively mild and operationally simple, requiring only reactions at room temperature for six hours (TFA) or overnight (HCl).Work is underway to further optimize these conditions and explore the scope of this reaction with a wider range of F-BODIPY derivatives.

Figure 1 :
Figure 1: An ORTEP plot of nitro-F-BODIPY 8 at the 50% probability level.A CIF file for the structure determination is available as Supporting Information File 2 and is also available on request from the Cambridge Crystallographic Data Centre as deposition 1018518. 3
a Extended reaction time (48 hours) was required.b Analytically pure material was obtained by HPLC purification.