Facile deprotection of F-BODIPYs using methylboronic acid

Abstract

4,4-Difluoro-4-bora-3a,4a-diaza-s-indacenes (F-BODIPYs) are deprotected through removal of the –BF₂ moiety upon treatment with methylboronic acid. The tolerance of various substitution patterns about the dipyrrinato core is demonstrated via the deprotection of thirteen F-BODIPYs and an F-aza-BODIPY. Work-up with aq. HBr affords the desired dipyrin HBr salt in quantitative yield without need for purification.

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Introduction

The dipyrrinato framework is a useful ligand for complexation to metals, the most common featuring first-row transition metals and boron.^1–4 The photophysical characteristics of –BF₂ complexes of dipyrrins, known widely as 4,4-difluoro-4-bora-3a,4a-diaza-s-indacenes (F-BODIPYs), have enabled applications across many of the chemical sciences.^5–8 For example, F-BODIPYs have been used as dyes to label proteins,⁹ DNA¹⁰ and functional materials.¹¹ Furthermore, the potential of F-BODIPYs for use in photo-assisted rechargeable batteries has been investigated.¹² Recently, efforts have focused on substituting the boron centre of BODIPYs with alkyl, alkynyl and chloro substituents in order to tune spectroscopic properties and thus potentially extend the performance of these conjugated chemical species.^13–25

Parallel to the photophysical and spectroscopic advances that have involved BODIPYs, dipyrrins have emerged as capable of providing a useful structural framework for incorporation into catalysts,^26–29 supramolecular assembles,^30,31 and polypyrroles with desirable biological activity.^32–35 As such, there is a desire to substitute, functionalise and manipulate dipyrrins, en route to accessing the dipyrrinato ligand. Given the broad range of strategies by which to functionalise F-BODIPYs, as well as the facile manner by which to purify them using chromatography, the use of the –BF₂ moiety has emerged as a useful approach to the protection of dipyrrins.^36–44 Reported methods for the removal of the –BF₂ moiety from F-BODIPYs, i.e. deprotection to yield the parent dipyrrin, have involved the use of alkoxides and strong Brønstead and Lewis acids. Herein, we report using methylboronic acid to deprotect thirteen F-BODIPYs and an F-aza-BODIPY to generate the corresponding dipyrrins and aza-dipyrrin in quantitative yield.

Results and discussion

Upon treating an F-BODIPY with methyl boronic acid, with anticipation that an appended boronic ester would be hydrolysed,⁴⁵ a dipyrrin was isolated as a result of removal of the –BF₂ unit. Cognisant that these conditions represent a mild alternative to existing methods for the deprotection of F-BODIPYs, and in light of the fact that the volatility of methylboronic acid renders work-up facile, we investigated the scope of the reaction conditions. Treatment of 4,4-difluoro-8-phenyl-4-bora-3a,4a-diaza-s-indacene (1a) with 5 equiv. methylboronic acid at room temperature (Table 1) gave clean conversion, after 24 hours, to provide the corresponding dipyrrin 2a in quantitative yield (entry 1). The incorporation of alkyl groups about the pyrrolic units was well tolerated, as was a methyl substituent in the meso-position (entries 2 and 3, respectively). Work-up using aqueous HBr provided the corresponding dipyrrin salts which are known to be more stable and more crystalline than their HX counterparts, an observation of significant value when storing meso-unsubstituted dipyrrins.⁴ Using these reaction conditions provided the meso-unsubstituted dipyrrin salts 2d and 2e in quantitative yield (entries 4 and 5, respectively). The preparation of the HBr salt of 2d was equally successful on a one-gram scale (entry 4). Furthermore, the corresponding free-base was isolated in quantitative yield, again on a one-gram scale, upon implementation of a basic work-up procedure. The removal of the –BF₂ unit using methylboronic acid was effective for F-BODIPYs bearing unsubstituted positions about the pyrrolic core (entry 6), as well as for unsymmetrical variants (entry 7). Given the previously documented sternutatory properties of the free base of 2f,³⁹ an alternative work-up procedure was implemented so as to ensure successful formation of the corresponding HBr salt. Dipyrrin 2g was also isolated in quantitative yield upon treatment of 4,4-difluoro-1,3-dimethyl-2-ethyl-6-pinacolatoboron-8-H-4-bora-3a,4a-diaza-s-indacene with 5 equiv. methylboronic acid, thereby effecting both deborylation (of the BPin moiety) as well as removal of the –BF₂ unit. The new method for the deprotection of F-BODIPYs proceeded in the presence of bromo-substituents, as exemplified by the isolation of quantitative yields of the dipyrrins 2h and 2i (entries 8 and 9). Similarly, the dipyrrin 2j was isolated in quantitative yield upon treatment of the corresponding F-BODIPY with methylboronic acid, thereby demonstrating tolerance of the hydroxy and trifluoromethyl functionalities within these electron-poor constructs. Further demonstration of the ability of methylboronic acid to deprotect F-BODIPYs bearing aryl substituents involved isolation of the two triphenyl-substituted dipyrrins 2k and 2l in quantitative yields (entries 11 and 12, respectively), with 2l being isolated as its free-base on account of the rather poor solubility of the corresponding HBr salt. Expanding the scope further, an aza-F-BODIPY i.e. a bridging nitrogen between the two pyrrolic sub-units, was successfully deprotected to provide the aza-dipyrrin 2m in quantitative yield (entry 13).

Table 1 Substrate scope for the deprotection of F-BODIPYs using methylboronic acid

Entry	Product dipyrrin salt yield (%)	Entry	Product dipyrrin salt yield (%)
a Work-up A involved quenching with 2 M aq. HBr.b Work-up B involved quenching with 1 M aq. HBr.c Work-up C involved quenching with sat. aq. NaHCO3.d Work-up involved quenching with 2 M aq. HBr performed on a gram scale.e Work-up quenching with sat. aq. NaHCO3 performed on a gram scale.f Using work-up A, dipyrrin 2g was prepared upon treatment of 4,4-difluoro-1,3-dimethyl-2-ethyl-6-pinacolatoboron-8-H-4-bora-3a,4a-diaza-s-indacene with 5 equiv. methylboronic thereby effecting both deborylation (of the BPin moiety) in addition to removal of the –BF2 unit.
1		8
2		9
3		10
4		11
5		12
6		13
7

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Attempts to reduce the equivalencies of the Lewis acid were briefly explored, resulting in the observation that 2d could be generated in quantitative yield upon treatment of the corresponding F-BODIPY with just 1 equiv. methylboronic acid. However, this achievement did not extend to the deprotection of F-BODIPYs appended with meso-aryl substituents. Despite the successful deprotection of thirteen F-BODIPYs and one F-aza-BODIPY using 5 equiv. methylboronic acid, the bromo-substituted F-BODIPY 3 (Fig. 1) reacted sluggishly to result in decomposition. Equally unsuccessful were attempts to use methylboronic acid to remove the –BF₂ unit from F-BODIPYs bearing carboxylate- or azido- functionality around the dipyrrolic core.

Fig. 1 Bromo-substituted F-BODIPY.

Conclusion

In conclusion, we have developed a high yielding and mild method for the deprotection of F-BODIPYs through the use of volatile methylboronic acid using 5% TFA and CH₂Cl₂ as solvent. The reaction is performed at room temperature, tolerates substrates bearing a range of substituents around the F-BODIPY framework, and requires only a facile work-up procedure in order to isolate quantitative yields of the dipyrrin as either an HBr salt or a free-base.

Experimental section

General information

Reactions involving air-sensitive reagents and dry solvents were performed using glassware that had been oven-dried (150 °C) or flame-dried prior to use. NMR spectra were recorded using a 500 MHz spectrometer. ¹H chemical shifts are reported in ppm relative to tetramethylsilane using the solvent residual as an internal standard (δ = 7.26 for CDCl₃; 5.32 for CD₂Cl₂; 2.05 for acetone-d₆; 2.50 for DMSO-d₆) ¹³C NMR chemical shifts are reported in ppm using the residual solvent as an internal standard (δ = 77.2 for CDCl₃; 53.8 for CD₂Cl₂; 29.8 for acetone-d₆; 39.5 for DMSO-d₆). Signals in NMR spectra are described as singlet (s), doublet (d), triplet (t), quartet (q), multiplet (m), broad (br.), apparent (app.) or a combination of these, referring to the observed spin–spin coupling pattern. Spin–spin coupling constants are reported in hertz (Hz), and are uncorrected. Mass spectrometry was performed using a TOF spectrometer operating in ESI⁺ or APCI mode, as indicated. Flash chromatography was performed using forced air flow of the indicated solvent system using silica gel 60 as solid support. Reactions were monitored by thin layer chromatography (TLC) on silica gel 60-covered aluminium sheets. TLC plates were developed under UV-light and/or with an acidic ethanolic anisaldehyde solution, vanillin or a KMnO₄-solution upon heating. All reagents were purchased from commercial suppliers and used without further purification unless otherwise stated. F-BODIPYs 1a,¹ 1b,² 1c,³ 1d,⁴ 1f,⁵ 1g,⁶ 2h,¹ 2j ⁷ and 2k ⁸ were prepared according to literature procedures, as was F-aza-BODIPY 1m.⁹

(Z)-4-Bromo-2-((4-ethyl-3,5-dimethyl-2H-pyrrol-2-ylidene)methyl)-1H-pyrrole hydrobromide

Following a modified literature procedure,¹⁰ to a round-bottom flask was added 3-ethyl-2,4-dimethyl-pyrrole (1.73 g, 14.1 mmol) and 4-bromo-pyrrole-2-carbaldehyde (2.44 g, 14.1 mmol). The pyrroles were dissolved in THF : MeOH (1 : 1; 85 mL), and the resulting solution was purged with nitrogen before 48% aq. HBr (3.2 mL, 28 mmol) was added drop-wise to the solution. The reaction mixture was stirred at 70 °C for 2 hours, monitoring by TLC analysis until complete consumption of starting material was observed. The reaction mixture was then poured into diethyl ether (100 mL) to induce precipitation. The resulting solid was collected by suction filtration, and dried to afford the title compound as a brown solid (3.60 g, 71%). ¹H NMR (500 MHz; CDCl₃) δ (ppm): 13.67 (s, 1H), 13.42 (s, 1H), 7.49 (s, 1H), 7.13 (s, 1H), 7.04 (s, 1H), 2.75 (s, 3H), 2.45 (q, J = 7.6 Hz, 2H), 2.30 (s, 3H), 1.09 (t, J = 7.6 Hz, 3H); ¹³C NMR (125 MHz; CDCl₃) δ (ppm): 164.9, 146.4, 135.6, 134.7, 130.7, 130.7, 130.3, 127.0, 101.8, 17.4, 14.1, 13.8, 10.4; HRMS-ESI (m/z): [M + H]⁺ calcd for C₁₃H₁₆BN₂, 279.0491; found, 279.0497.

4,4-Difluoro-1,3-dimethyl-2-ethyl-6-bromo-8-H-4-bora-3a,4a-diaza-s-indacene

Following a literature procedure,⁴ to a solution of (Z)-4-bromo-2-((4-ethyl-3,5-dimethyl-2H-pyrrol-2-ylidene)methyl)-1H-pyrrole hydrobromide (3.60 g, 10.0 mmol) in CH₂Cl₂ (180 mL) under air with stirring at room temperature, was added NEt₃ (8.4 mL, 60 mmol) and the resulting solution stirred for 10 minutes. Anhydrous BF₃·OEt₂ (11 mL, 90 mmol) was then added and the reaction mixture was sealed with a septum and stirred for 1 hour. The septum was then removed, and another aliquot of NEt₃ (8.4 mL, 60 mmol) was added. The vessel was resealed and stirred for 10 minutes, after which the septum was again removed and another aliquot of anhydrous BF₃·OEt₂ (11.1 mL, 90 mmol) was added. The resulting solution was sealed again and stirred for another 1 hour. The reaction mixture was concentrated in vacuo to yield the crude product, which was dissolved in ether (60 mL). The resulting solution washed with 1 M aq. hydrochloric acid (4× 50 mL) and 5 M aq. hydrochloric acid (1× 50 mL). The organic fraction was dried over anhydrous Na₂SO₄ and concentrated in vacuo. The crude material was purified via column chromatography on silica (hexanes/CH₂Cl₂; 1 : 1) to afford the title compound as a red solid (2.30 g, 62%). ¹H NMR (500 MHz; CDCl₃) δ (ppm): 7.44 (s, 1H), 7.02 (s, 1H), 6.77 (s, 1H), 2.58 (s, 3H), 2.41 (q, J = 7.6 Hz, 2H), 2.19 (s, 3H), 1.09 (t, J = 7.6 Hz, 3H); ¹³C NMR (125 MHz; CDCl₃) δ (ppm): 166.2, 142.3, 137.2, 136.1, 136.0, 131.8, 124.4, 122.6, 102.7, 17.4, 14.2, 13.7, 9.7; ¹¹B NMR (160 MHz; CDCl₃) δ (ppm): 0.3 (t, J = 31 Hz); ¹⁹F NMR (470 MHz; CDCl₃) δ (ppm): −146.1 (q, J = 31 Hz); HRMS-APCI (m/z): [M + H]⁺ calcd for C₁₃H₁₅BBrF₂N₂, 327.0474; found, 327.0478.

4,4-Difluoro-1,3-dimethyl-2-ethyl-6-pinacolatoboron-8-H-4-bora-3a,4a-diaza-s-indacene

A 4 mL screw-top vial was charged with 4,4-difluoro-1,3-dimethyl-2-ethyl-6-bromo-8-H-4-bora-3a,4a-diaza-s-indacene (163 mg, 0.5 mmol), Pd₂(dba)₃ (5 mg, 5 μmol), XPhos (9 mg, 20 μmol), bis(pinacolato)diboron (380 mg, 1.50 mmol) and oven dried KOAc (147 mg, 1.50 mmol). The vial was capped with a septum and then evacuated and backfilled with N₂ (this sequence was carried out two times). 1,4-Dioxane (3 mL) was added via syringe through the septum. Under a flow of nitrogen, the septum was replaced with a screw cap. The reaction mixture was stirred at 110 °C in a preheated aluminium block until consumption of the F-BODIPY starting material was complete, as judged by TLC analysis (approximately 20 minutes). The reaction mixture was allowed to cool to room temperature and then filtered through a thin pad of Celite, eluting with CH₂Cl₂. The crude material was purified via rapid chromatography on silica (hexanes : EtOAc; 8 : 2), with minimal residence time ensured in order to minimise decomposition over the solid phase. The product was crystallised from hexanes to give the title compound as a bench- and air-stable brown solid (113 mg, 60%). ¹H NMR (500 MHz; CDCl₃) δ (ppm): 7.96 (s, 1H), 7.22 (s, 1H), 7.17 (s, 1H), 2.61 (s, 3H), 2.45 (q, J = 7.6 Hz, 2H), 2.24 (s, 3H), 1.36 (s, 12H), 1.12 (t, J = 7.6 Hz, 3H); ¹³C NMR (125 MHz; CDCl₃) δ (ppm): 164.2, 145.2, 141.4, 136.9, 135.5, 133.5, 131.8, 123.6, 83.5, 25.0, 17.5, 14.3, 13.5, 9.7, 1× Ar C signal missing; ¹¹B NMR (160 MHz; CDCl₃) δ (ppm): 30.4 (br. s) 0.6 (t, J = 32 Hz); ¹⁹F NMR (470 MHz; CDCl₃) δ (ppm): −146.0 (q, J = 31 Hz); HRMS-APCI (m/z): [M + H]⁺ calcd for C₁₉H₂₇B₂F₂N₂O₂, 375.2221; found, 375.2234.

4,4-Difluoro-1,3,5,7-tetramethyl-2-ethyl-6-bromo-8-H-4-bora-3a,4a-diaza-s-indacene (1i)

To a 100 mL round-bottom flask, charged with a magnetic stirrer bar, was added 4,4-difluoro-1,3,5,7-tetramethyl-2-ethyl-8-H-4-bora-3a,4a-diaza-s-indacene¹¹ (730 mg, 2.64 mmol) and CH₂Cl₂ (37 mL). To the solution was added N-bromosuccinimide (469 mg, 2.64 mmol). The reaction mixture was stirred at room temperature for 1 hour, then quenched with H₂O (30 mL) and extracted with CH₂Cl₂ (3× 50 mL). The combined organic fractions were dried over Na₂SO₄, filtered and concentrated in vacuo. The crude material was purified via column chromatography on silica (hexanes/CH₂Cl₂; 8 : 2) to afford the title compound as a red solid (906 mg, 97%). ¹H NMR (500 MHz; CDCl₃) δ (ppm): 6.98 (s, 1H), 2.53 (s, 3H), 2.52 (s, 3H), 2.39 (q, J = 7.6 Hz, 2H), 2.19 (s, 3H), 2.17 (s, 3H), 1.07 (t, J = 7.6 Hz, 3H); ¹³C NMR (125 MHz; CDCl₃) δ (ppm): 159.5, 150.8, 139.3, 136.3, 134.1, 133.7, 130.6, 119.5, 107.6, 17.4, 14.5, 13.3, 13.1, 11.0, 9.6; ¹¹B NMR (160 MHz; CDCl₃) δ (ppm): 0.7 (t, J = 33 Hz); ¹⁹F NMR (470 MHz; CDCl₃) δ (ppm): −146.4 (q, J = 33 Hz); HRMS-APCI (m/z): [M + H]⁺ calcd for C₁₅H₁₉BBrF₂N₂, 355.0787; found, 355.0781.

General procedure (GP) for the deprotection of F-BODIPYs using MeB(OH)₂

A 4 mL screw-top vial was charged with F-BODIPY (0.2 mmol) and MeB(OH)₂ (1.0 mmol). To this was added CH₂Cl₂ (1.90 mL) and trifluoroacetic acid (0.10 mL). The vial was capped with a screw cap and the mixture was stirred until F-BODIPY had been completely consumed as judged by analysis using TLC (typically stirred for 24 hours).

Work-up A. The reaction mixture was transferred to a separatory funnel using CH₂Cl₂, quenched with 2 M aq. hydrobromic acid (40 mL) and the aqueous phase then extracted with CH₂Cl₂ (3× 40 mL). The combined organic extracts were dried over Na₂SO₄ and volatiles were then removed in vacuo to afford the dipyrrin HBr salt.

Work-up B. The reaction mixture was transferred into a 100 mL round-bottomed flask using CH₂Cl₂ and all volatiles removed in vacuo. To the 100 mL round-bottomed flask was added 1 M aq. hydrobromic acid (40 mL) which was then removed under reduced pressure, followed by the addition of CH₂Cl₂. After filtration of the resulting mixture, volatiles were removed in vacuo to afford the dipyrrin HBr salt.

Work-up C. The reaction mixture was transferred to a separatory funnel using CH₂Cl₂ and to the resulting solution was added sat. aq. NaHCO₃ (40 mL). The mixture was extracted with CH₂Cl₂ (3× 40 mL), the combined organic extracts dried over Na₂SO₄ and volatiles removed in vacuo to afford the dipyrrin as a free base.

(Z)-2-(Phenyl(2H-pyrrol-2-ylidene)methyl)-1H-pyrrole hydrobromide (2a)

Following the GP and work-up A, using 4,4-difluoro-8-phenyl-4-bora-3a,4a-diaza-s-indacene (1a),⁶ provided the title compound as a brown solid (60 mg, >99%). ¹H NMR (500 MHz; CDCl₃) δ (ppm): 13.43 (br. s, 2H), 8.09 (br. s, 2H), 7.64 (s, 1H), 7.51–7.45 (m, 4H), 6.81 (s, 2H), 6.63 (s, 2H); ¹³C NMR (125 MHz; CDCl₃) δ (ppm): 149.9, 143.9, 136.7, 133.9, 132.1, 131.6, 131.3, 128.2, 117.5; HRMS-ESI (m/z): [M + H]⁺ calcd for C₁₅H₁₃N₂, 221.1073; found, 221.1073.

(Z)-3-Ethyl-5-((4-ethyl-3,5-dimethyl-2H-pyrrol-2-ylidene)(phenyl)methyl)-2,4-dimethyl-1H-pyrrole hydrobromide (2b)

Following the GP and work-up A, using 4,4-difluoro-1,3,5,7-tetramethyl-2,6-diethyl-8-phenyl-4-bora-3a,4a-diaza-s-indacene (1b),² provided the title compound as a red solid (82 mg, > 99%).¹H NMR (500 MHz; CDCl₃) δ (ppm): 11.01 (br. s, 2H), 7.59 (t, J = 7.3 Hz, 1H), 7.48 (t, J = 7.3 Hz, 2H), 7.30 (d, J = 7.4 Hz, 2H), 2.70 (br. s, 6H), 2.41–2.35 (m, 4H), 1.36 (br. s, 6H), 1.06–1.03 (m, 6H); ¹³C NMR (125 MHz; CDCl₃) δ (ppm): 152.4, 144.2, 140.1, 137.1, 133.7, 131.8, 128.7, 129.0, 17.5, 14.5, 13.7, 12.3, 1× aryl signal missing; HRMS-ESI (m/z): [M + H]⁺ calcd for C₂₃H₂₉N₂, 333.2325; found, 333.2323.

(Z)-3-Ethyl-5-(1-(4-ethyl-3,5-dimethyl-2H-pyrrol-2-ylidene)ethyl)-2,4-dimethyl-1H-pyrrole hydrobromide (2c)

Following the GP and work-up A, using 4,4-difluoro-1,3,5,7,8-pentamethyl-2,6-diethyl-4-bora-3a,4a-diaza-s-indacene (1c),³ provided the title compound as a brown solid (70 mg, > 99%). ¹H NMR (500 MHz; CDCl₃) δ (ppm): 11.82 (br. s, 2H), 2.87 (s, 3H), 2.54 (s, 6H), 2.39 (q, J = 7.4 Hz, 4H), 2.05 (s, 6H), 1.05 (t, J = 7.4 Hz, 6H); ¹³C NMR (125 MHz; CDCl₃) δ (ppm): 149.2, 146.7, 137.1, 132.2, 131.5, 25.0, 17.6, 14.5, 12.7, 12.4. Data correspond to literature values.¹²

(Z)-3-Ethyl-5-((4-ethyl-3,5-dimethyl-2H-pyrrol-2-ylidene)methyl)-2,4-dimethyl-1H-pyrrole hydrobromide (2d)

Following the GP and work-up A, using 4,4-difluoro-1,3,5,7-tetramethyl-2,6-diethyl-4-bora-3a,4a-diaza-s-indacene (1d),⁴ provided the title compound as a brown solid (67 mg, > 99%). ¹H NMR (500 MHz; CDCl₃) δ (ppm): 12.87 (br. s, 2H), 7.01 (s, 1H), 2.64 (s, 6H), 2.40 (q, J = 7.6 Hz, 4H), 2.25 (s, 6H), 1.05 (t, J = 7.6 Hz, 6H); ¹³C NMR (125 MHz; CDCl₃) δ (ppm): 153.7, 141.3, 130.6, 126.1, 118.7, 17.3, 14.5, 12.8, 10.1. Data correspond to literature values.¹³

(Z)-3-(3,3-Dimethylbutyl)-5-((4-(3,3-dimethylbutyl)-3,5-dimethyl-2H-pyrrol-2-ylidene)methyl)-2,4-dimethyl-1H-pyrrole hydrobromide (2e)

Following the GP and work-up A, using, 4-difluoro-1,3,5,7-tetramethyl-2,6-(3,3-dimethylbutyl)-4-bora-3a,4a-diaza-s-indacene (1e), provided the title compound as a red solid (90 mg, > 99%). ¹H NMR (500 MHz; CD₂Cl₂) δ (ppm): 12.92 (br. s, 2H), 7.06 (s, 1H), 2.59 (s, 6H), 2.36–2.33 (m, 4H), 2.27 (s, 6H), 1.28–1.25 (m, 4H), 0.97 (s, 18H); ¹³C NMR (125 MHz; CD₂Cl₂) δ (ppm): 153.4, 141.5, 129.5, 126.0, 118.7, 44.0, 30.3, 28.8, 19.1, 12.5, 10.3; HRMS-ESI (m/z): [M + H]⁺ calcd for C₂₅H₄₁N₂, 369.3264; found, 369.3278.

(Z)-2-((3,5-Dimethyl-2H-pyrrol-2-ylidene)methyl)-3,5-dimethyl-1H-pyrrole hydrobromide (2f)

Following the GP and work-up B, using 4,4-difluoro-1,3,5,7-tetramethyl-4-bora-3a,4a-diaza-s-indacene (1f),² provided the title compound as a red solid (56 mg, > 99%). ¹H NMR (500 MHz; CDCl₃) δ (ppm): 13.06 (br. s, 2H), 7.07 (s, 1H), 6.14 (s, 2H), 2.66 (s, 6H), 2.34 (s, 6H); ¹³C NMR (125 MHz; CDCl₃) δ (ppm): 155.6, 146.1, 126.8, 120.1, 117.6, 14.6, 12.3. Data correspond to literature values.¹⁴ Caution: the free-base of 2f has been reported to exhibit sternutatory properties.⁷

(Z)-2-((4-Ethyl-3,5-dimethyl-2H-pyrrol-2-ylidene)methyl)-1H-pyrrole hydrobromide (2g)

Following the GP and work-up A, using 4,4-difluoro-1,3-dimethyl-2-ethyl-4-bora-3a,4a-diaza-s-indacene (1g),¹⁵ provided the title compound as a red solid (56 mg, > 99%). ¹H NMR (500 MHz; CDCl₃) δ (ppm): 13.50 (br. s, 1H), 13.31 (br. s, 1H), 7.65 (s, 1H), 7.21 (s, 1H), 7.09 (s, 1H), 6.47 (s, 1H), 2.73 (s, 3H), 2.43 (q, J = 7.5 Hz, 2H), 2.29 (s, 3H), 1.08 (t, J = 7.5 Hz, 3H); ¹³C NMR (125 MHz; CDCl₃) δ (ppm): 162.0, 145.4, 137.6, 133.6, 132.1, 129.3, 127.3, 124.8, 114.6, 17.3, 14.2, 13.6, 10.3. Data correspond to literature values.¹⁰

Alternatively, following the GP and work-up A using 4,4-difluoro-1,3-dimethyl-2-ethyl-6-pinacolatoboron-8-H-4-bora-3a,4a-diaza-s-indacene provided the title compound as a red solid (56 mg, > 99%). Data as above.

(Z)-2-((4-Bromophenyl)(2H-pyrrol-2-ylidene)methyl)-1H-pyrrole hydrobromide (2h)

Following the GP and work-up A, using 4,4-difluoro-8-(phenyl(4-bromo))-4-bora-3a,4a-diaza-s-indacene (1h),⁷ provided the title compound as a red solid (76 mg, > 99%).¹H NMR (500 MHz; CDCl₃) δ (ppm): 13.48 (br. s, 2H), 8.10 (br. s, 2H), 7.66 (d, J = 6.3 Hz, 2H), 7.29 (br. s, 2H), 6.81 (br. s, 2H), 6.65 (s, 2H); ¹³C NMR (125 MHz; CDCl₃) δ (ppm): 148.2, 144.4, 136.3, 135.3, 133.5, 131.6, 131.0, 126.6, 117.8.

(Z)-3-Bromo-5-((4-ethyl-3,5-dimethyl-2H-pyrrol-2-ylidene)methyl)-2,4-dimethyl-1H-pyrrole hydrobromide (2i)

Following the GP and work-up B, using 4,4-difluoro-1,3,5,7-tetramethyl-2-ethyl-6-bromo-8-H-4-bora-3a,4a-diaza-s-indacene (1i), provided the title compound as a red solid (78 mg, > 99%). ¹H NMR (500 MHz; CDCl₃) δ (ppm): 13.20 (br. s, 2H), 7.08 (s, 1H), 2.67 (s, 3H), 2.64 (s, 3H), 2.42 (q, J = 7.6 Hz, 2H), 2.32 (s, 3H), 2.29 (s, 3H), 1.07 (t, J = 7.6 Hz, 3H); ¹³C NMR (125 MHz; CDCl₃) δ 158.2, 150.3, 143.7, 141.1, 132.3, 127.4, 124.8, 119.8, 106.6, 17.4, 14.3, 13.4, 13.2, 11.9, 10.3; HRMS-ESI (m/z): [M + H]⁺ calcd for C₁₅H₂₀BrN₂, 307.0804; found, 307.0803.

(Z)-1-(2-((4-Ethyl-3,5-dimethyl-1H-pyrrol-2-yl)methylene)-3,5-dimethyl-2H-pyrrol-4-yl)-2,2,2-trifluoroethanol hydrobromide (2j)

Following the GP and work-up B, using 4,4-difluoro-1,3,5,7-tetramethyl-2-trifluoroethanol-6-ethyl-4-bora-3a,4a-diaza-s-indacene (1j),⁷ provided the title compound as a red solid (81 mg, > 99%). ¹H NMR (500 MHz; acetone-d₆) δ (ppm): 13.75 (br. s, 1H), 13.53 (br. s, 1H), 7.44 (s, 1H), 5.86 (d, J = 5.0 Hz, 1H), 5.39–5.33 (m, 1H), 2.72 (s, 3H), 2.69 (s, 3H), 2.51 (q, J = 7.5 Hz, 2H), 2.46 (s, 3H), 2.39 (s, 3H), 1.11 (t, J = 7.5 Hz, 3H); ¹³C NMR (125 MHz; acetone-d₆) δ (ppm): 158.5, 152.5, 145.0, 144.0, 132.8, 128.1, 126.4 (q, J = 281 Hz), 125.9, 121.4, 110.8, 66.8 (q, J = 33 Hz), 17.6, 14.5, 13.3, 12.8, 10.6, 10.1; ¹⁹F NMR (470 MHz; acetone-d₆) δ (ppm): −78.4 (d, J = 7.6 Hz). Data correspond to literature values.¹⁶

(Z)-2-Phenyl-5-(phenyl(5-phenyl-2H-pyrrol-2-ylidene)methyl)-1H-pyrrole hydrobromide (2k)

Following the GP and work-up C, using 4,4-difluoro-2,5,8-triphenyl-4-bora-3a,4a-diaza-s-indacene (1k),⁸ provided the title compound as a red solid (90 mg, > 99%). ¹H NMR (500 MHz; acetone-d₆) δ (ppm): 13.05 (br. s, 2H), 8.36–8.29 (m, 4H), 7.74 (t, J = 7.2 Hz, 1H), 7.62 (t, J = 7.6 Hz, 2H), 7.57 (d, J = 7.4 Hz, 2H), 7.53–7.50 (m, 6H), 7.33 (s, 2H), 7.20–6.90 (m, 2H); ¹³C NMR (125 MHz; acetone-d₆) δ (ppm): 154.6, 147.2, 137.8, 135.8, 135.1, 134.8, 133.5, 131.7, 130.0, 129.8, 129.5, 129.2, 117.9; HRMS-ESI (m/z): [M + H]⁺ calcd for C₂₇H₂₁N₂, 373.1699; found, 373.1702.

(Z)-4-Phenyl-2-(phenyl(4-phenyl-2H-pyrrol-2-ylidene)methyl)-1H-pyrrole (2l)

Following the GP and work-up C, using 4,4-difluoro-3,6,8-triphenyl-4-bora-3a,4a-diaza-s-indacene (1l), provided the title compound as a dark blue solid (74 mg, >99%). ¹H NMR (500 MHz; DMSO-d₆) δ (ppm): 8.28 (s, 2H), 7.62–7.57 (m, 9H), 7.36–7.33 (m, 4H), 7.23–7.20 (m, 2H), 6.76 (s, 2H); HRMS-ESI (m/z): [M + H]⁺ calcd for C₂₇H₂₁N₂, 373.1699; found, 373.1699. The title compound was insufficiently soluble to enable the acquisition of ¹³C NMR data.

(Z)-N-(3,5-Diphenyl-2H-pyrrol-2-ylidene)-3,5-diphenyl-1H-pyrrol-2-amine (2m)

Following the GP and work-up C, using 4,4-difluoro-1,3,5,7-tetraphenyl-4-bora-3a,4a,8-triaza-s-indacene (1m),⁹ provided the title compound as a dark blue solid (90 mg, >99%). ¹H NMR (500 MHz; CDCl₃) δ (ppm): 8.07 (d, J = 7.3 Hz, 4H), 7.96 (d, J = 7.4 Hz, 4H), 7.54 (t, J = 7.5 Hz, 4H), 7.48 (d, J = 7.4 Hz, 2H), 7.43 (t, J = 7.5 Hz, 4H), 7.36 (t, J = 7.3 Hz, 2H), 7.21 (s, 2H); ¹³C NMR (125 MHz; CDCl₃) δ (ppm): 155.3, 149.8, 142.8, 133.9, 132.4, 130.2, 129.3, 129.2, 128.4, 128.2, 126.7, 115.1. Data correspond to literature values.¹⁷

Conflicts of interest

The authors declare no competing financial interest.

Acknowledgements

Financial support for this work was provided by NSERC of Canada via a Discovery Grant and the CREATE Training Program in BioActives (510963). Dr Mike Lumsden and Mr Xiao Feng (both at Dalhousie University) are thanked for sharing their expertise in NMR spectroscopy and mass spectrometry, respectively.

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Footnote

† Electronic supplementary information (ESI) available: Images of NMR spectra. See DOI: 10.1039/d0ra05151a

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