Efficient deprotection of F-BODIPY derivatives: Removal of BF2 using bronsted acids

Article abstract of DOI:10.3762/bjoc.11.6

The effective and efficient removal of the BF₂ moiety from F-BODIPY derivatives has been achieved using two common Bronsted acids; treatment with trifluoroacetic acid (TFA) or methanolic hydrogen chloride (HCl) followed by work-up with Ambersep

Full text of DOI:10.3762/bjoc.11.6

Efficient deprotection of F-BODIPY derivatives: removal of
BF2 using Brønsted acids
Mingfeng Yu1, Joseph K.-H. Wong1, Cyril Tang1, Peter Turner2, Matthew H. Todd*1
and Peter J. Rutledge*1
Letter
Open Access
Address:
Beilstein J. Org. Chem. 2015, 11, 37–41.
1School of Chemistry, The University of Sydney, Sydney, New South
Wales 2006, Australia and 2Crystal Structure Analysis Facility, School
of Chemistry, The University of Sydney, Sydney, New South Wales
2006, Australia
doi:10.3762/bjoc.11.6
Received: 22 September 2014
Accepted: 22 December 2014
Published: 09 January 2015
Email:
Matthew H. Todd* - matthew.todd@sydney.edu.au;
Peter J. Rutledge* - peter.rutledge@sydney.edu.au
Associate Editor: D. O'Hagan
© 2015 Yu et al; licensee Beilstein-Institut.
License and terms: see end of document.
* Corresponding author
Keywords:
Brønsted acids; click chemistry; deboration; dipyrrins; F-BODIPYs
Abstract
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 rela-
tively mild and operationally simple, requiring only reaction at room temperature for six hours (TFA) or overnight (HCl).
Findings
Compounds incorporating the 4,4-difluoro-4-bora-3a,4a-diaza- difficult to handle but have a range of potential applications in
s-indacene (F-BODIPY) motif 1 have found widespread use in dye and porphyrin syntheses, metal ion coordination and supra-
fluorescent molecular probes [1,2], photovoltaic devices [3,4] molecular chemistry [12]. Methods to enable the functionaliza-
and photodynamic therapy agents [5-8]. Accordingly, there is tion of dipyrrins by temporarily complexing with tin or zinc
considerable interest in extending and diversifying the have been investigated [13,14]. More recently, the F-BODIPY
F-BODIPY framework [9]. F-BODIPYs are readily prepared by motif has been envisaged as a means of protecting the dipyrrin,
condensing aldehydes, acyl chlorides or anhydrides with to enable chemical modification and purification before
pyrroles and trapping the resulting dipyrrin in situ with boron removal of the BF2 unit (i.e., deprotection) to reveal the func-
trifluoride [9-11]. F-BODIPYs are generally stable and chemi- tionalized dipyrrin. With this goal in mind, several recent
cally robust, with photophysical properties that facilitate reports have detailed methods for converting F-BODIPYs 1 to
chromatographic purification. The parent dipyrrins are more the parent dipyrrins 2 (Scheme 1) [15-19].
37

Beilstein J. Org. Chem. 2015, 11, 37–41.
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].
Scheme 1: Conversion of F-BODIPYs 1 to the parent dipyrrins 2.
Herein we report the effective and efficient removal of the BF2
moiety from F-BODIPY derivatives using two common
Crawford and Thompson first proposed the BF2 unit as a Brønsted acids: treatment with trifluoroacetic acid (TFA) or
protecting group for dipyrrins in 2010, and applied strong base methanolic hydrogen chloride (HCl) at room temperature fol-
under forcing conditions to effect the deprotection: potassium lowed by work-up with Ambersep® 900 resin (hydroxide form)
tert-butoxide in tert-butanol/water with microwave heating to achieves this conversion in near-quantitative yields.
90–140 °C (26–98% yield) [15,16]. Kusaka et al. built on this
strategy to achieve deboration of F-BODIPYs using sodium We have an ongoing interest in triazolyl-cyclam derivatives
tert-butoxide in refluxing toluene (59–83% yield) en route to incorporating fluorescent dyes for sensing applications [22-25].
bis(dipyrrinato)zinc(II) complexes [17]. Two very recent Looking to extend these systems to incorporate an F-BODIPY
reports have deployed Lewis acids to achieve this transforma- motif, we have synthesized the Boc-protected triazolyl-cyclam/
tion: Thompson and co-workers used boron trihalides in F-BODIPY derivatives 3 and 4 from 2,4-dimethyl-1H-pyrrole
dichloromethane under anhydrous conditions, followed by treat- (5), 4-nitrobenzaldehyde (6, Scheme 2A) and 4-bromobenzalde-
ment with acetone/water (10:1) to achieve quantitative removal hyde (7, Scheme 2B) respectively (see Supporting Information
of the BF2 moiety [18]; Ravikanth and co-workers screened a File 1 for experimental data).
range of metal-based Lewis acids (ZrCl4, TiCl4, AlCl3,
Sc(OTf)3, SnCl4) and reported yields up to 96% using ZrCl4 in Preparation of nitro-F-BODIPY 8 was initially attempted by
refluxing methanol/acetonitrile [19].
adapting the reported synthetic method [10]. However the ethe-
Scheme 2: Synthesis of the triazolyl-cyclam/F-BODIPY conjugates 3 (A) and 4 (B). Reagents and conditions: (a) (i) 2,4-dimethyl-1H-pyrrole (5), TFA,
DCM, rt, overnight; (ii) DDQ, rt, 2 h; (iii) Et3N, BF3·OEt2, rt, overnight, 27%; (b) NH2NH2·H2O, 10% Pd/C, EtOH, reflux, 2 h, 90%; (c) (i) 1 M HCl (aq),
CH3OH, NaNO2, H2O, 0 °C, 1 h; (ii) NaN3, H2O, rt, 2 h, 71%; (d) propargyl-tri-Boc cyclam 12, CuSO4·5H2O, sodium ascorbate, THF/H2O (7:3), 50 °C,
12 h, 100%; (e) trimethylsilylacetylene, CuI, Pd(PPh3)4, Et3N, THF, rt, overnight, 100%; (f) K2CO3, CH3OH, rt, overnight, 71%; (g) (i) 2,4-dimethyl-1H-
pyrrole (5), TFA, DCM, rt, overnight; (ii) DDQ, rt, 2 h; (iii) Et3N, BF3·OEt2, rt, overnight, 24%; (h) 2-azidoethyl-tri-Boc cyclam 13, CuSO4·5H2O, sodium
ascorbate, THF/H2O (7:3), 50 °C, 12 h, 91%.
38

Beilstein J. Org. Chem. 2015, 11, 37–41.
real complex 8·Et2O was isolated by flash column chromatog- In attempting to remove the Boc groups from 3 and 4, we have
raphy, rather than 8 itself (readily evident in the 1H and discovered a facile method for the removal of BF2 from these
13C NMR spectra). To the best of our knowledge, the com- F-BODIPY derivatives using Brønsted acids (Scheme 3,
plexation of Et2O in this way has not been reported in previous Table 1) (see Supporting Information File 1 for experimental
syntheses of F-BODIPY derivatives. Considering that the same data). Thus 3 was converted efficiently to 14 (96–99% yield)
procedures were used to synthesize and purify 8 as we used to with the loss of three Boc groups and the BF2 moiety, using
prepare 11 free from Et2O (vide infra), and given previous either a mixture of TFA/DCM/H2O (90:5:5) or a methanolic
reports on the ability of nitrogen oxides (e.g., NO, N2O3 and solution of hydrogen chloride (2.8 M) at room temperature, fol-
N2O4) to complex with boron trifluoride [26-29], the nitro lowed by basification with a suspension of excess Ambersep®
group is presumably the key factor in the complexation of 8 900 resin (hydroxide form) in methanol. Similarly, 4 afforded
with Et2O. Washing with aqueous and organic solvents did not 15 (96–98% yield) under the same reaction conditions.
completely remove the complexed ether, but uncomplexed 8
was obtained after recrystallization from ethyl acetate. The In an initial investigation of the scope of this transformation,
structure of this F-BODIPY derivative was determined by NMR each of the F-BODIPY derivatives prepared in this study was
and X-ray crystallography (Figure 1), and its purity confirmed subjected to the reaction conditions that rendered BF2-removal
by elemental analysis. Conversion of the nitro compound 8 to from 3 and 4 (Scheme 3, Table 1). Nitro-F-BODIPY 8 was
the corresponding azide 9 was achieved by palladium-catalyzed readily converted to dipyrrin 16 by the TFA method in quanti-
reduction [10] followed by diazotization of the amine and tative yield (100%). With this substrate, the HCl method
subsequent substitution with azide [30]. 4-Bromobenzaldehyde required an extended reaction time (48 hours) to give 16 in
(7) was readily converted to ethynyl-F-BODIPY 11 according excellent yield (92%). Near-quantitative (99%) conversion of
to the literature procedures [11,31]. Azido-F-BODIPY 9 and azido-F-BODIPY 9 to dipyrrin 17 was achieved using both
ethynyl-F-BODIPY 11 were reacted respectively with the methods. Ethynyl-F-BODIPY 11 was successfully converted to
complementary propargyl-tri-Boc cyclam 12 [23,32] and dipyrrin 18 using both Brønsted acids: LC–MS analysis (see
2-azidoethyl-tri-Boc cyclam 13 [24,25] under the modified click Supporting Information File 1) revealed the desired 18 as the
conditions we have reported previously [24] to generate the major product at m/z 301.2, however, the crude product also
Boc-protected triazolyl-cyclam/F-BODIPY conjugates 3 and 4 contained a minor contaminant at m/z 319.3, consistent with
in excellent yields.
addition of water to the alkyne. 1H NMR analysis indicated that
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 Infor-
mation File 2 and is also available on request from the Cambridge Crystallographic Data Centre as deposition 1018518.
39

Beilstein J. Org. Chem. 2015, 11, 37–41.
Scheme 3: Conversion of F-BODIPYs to dipyrrins using Brønsted acids. Reagents and conditions: (a) (i) TFA/DCM/H2O (90:5:5), rt, 6 h; or 2.8 M HCl
in CH3OH, rt, 12–48 h; (ii) Ambersep® 900 resin (hydroxide form), CH3OH, rt, 15 min (see Table 1 for yields).
simple, requiring only reactions at room temperature for six
Table 1: Removal of BF2 from F-BODIPYs using Brønsted acids.
hours (TFA) or overnight (HCl). Work is underway to further
F-BODIPY
dipyrrin
yield (%)
optimize these conditions and explore the scope of this reaction
with a wider range of F-BODIPY derivatives.
TFA
HCl
3
4
14
15
16
17
18
99
96
96
98
Supporting Information
8
100
99
92a
99
Supporting Information File 1
9
Experimental procedures and characterization data;
crystallographic information for 8; 1H, 13C, 11B & 19F
NMR spectra of novel compounds 3, 4, 14, 15, 16–18;
LC–MS trace of crude 18.
11
53b
53b
aExtended reaction time (48 hours) was required. bAnalytically pure
material was obtained by HPLC purification.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-11-6-S1.pdf]
this impurity was present at ≤5% abundance, but HPLC purifi-
cation was required to generate analytically pure 18 which
compromised the final yields (53% for both methods).
Supporting Information File 2
CIF file of 8, CCDC 1018518.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-11-6-S2.cif]
We are aware of two previous reports investigating the treat-
ment of BODIPYs with Brønsted acids. Yang et al. used
11B NMR to monitor the stability of BODIPYs in the presence
of di- or trichloroacetic acid, reporting ‘partial decomposition’ Acknowledgements
of an F-BODIPY derivative without characterizing the break- We thank the National Breast Cancer Foundation for a Novel
down product(s) [33]. While Liras et al. reported the synthesis Concept Grant (NC-10-69) and the Australian Research Council
of a single aminodipyrrin product from the corresponding for funding (DP120104035). M. Yu was supported by a Univer-
3-amino- and 3-acetamido-F-BODIPY precursors, using ‘HCl- sity of Sydney International Scholarship (USydIS) and J. K.-H.
catalyzed deacetylation conditions’ (HCl in ethanol) to effect Wong by an Australian Postgraduate Award (APA) from the
both deacetylation and deboration [34].
Australian Government.
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