Solution and solid-state fluorescence of 2-(2′-hydroxyphenyl)-1,5-benzodiazepin-2-one (HBD) borate complexes

Abstract

A new family of fluorescent 1,5-benzodiazepin-2-one (HBD) borate complexes was prepared in good yields, and fully characterized by means of MS, NMR and IR spectroscopy, as well as X-ray crystal structure analysis for compound 13. Unlike their uncomplexed congeners, most of these cyclic boranils were emissive both in solution and the solid state, with maxima in the range of 426–596 nm. A systematic study of substituent effects revealed that the presence of a halogen atom specifically at position 8 of the fused-aromatic ring system led to an increase in fluorescence intensity in solution while electron rich substituents tended to extinguish the photoluminescence. Finally, a proof-of-concept study highlighted that the amide moiety of the benzodiazepinone framework could be functionalized with a chemical handle useful for subsequent specific modifications.

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1. Introduction

Fluorescent boron complexes are an intriguing family of fluorescent small organic molecules that have gained increasing attention in the past two decades due to their high potential for diverse photoluminescence applications including laser dyes, chemosensing¹ and biolabeling.² Furthermore, their charge transport ability was also leveraged in recent and promising applications encompassing dye-sensitized solar cells,³ organic light-emitting diodes, and data storage.⁴

In this context, well-known boron dipyrromethene (BODIPY) dyes have shown remarkable photophysical properties such as sharp absorption and emission spectra, high quantum yields, and excellent chemo- and photostability (not sensitive to their environment in terms of pH or polarity).⁵ However, these N–B–N bidentate complexes suffer from small Stokes' shifts because of their rigid molecular structures, causing self-quenching and low fluorescence in the solid state. Another drawback may come from their accessibility that occasionally turns out to be tedious. To circumvent these limitations and meet the growing demand for new photoluminescent structures, new generations of aryl-fused⁶ or bulky⁷ BODIPY have been reported as well as other families of N–B–N complexes including pyridomethene-,⁸ formazanate-,⁹ and aza-pyridyl-isoindoline-containing systems.¹⁰ More recently, chelates based on the O–B–O¹¹ and N–B–O¹² patterns were also investigated, among which boranils composed of phenoxy-anil ligands have emerged as a promising new family of fluorescent boron complexes (Scheme 1).¹³

Scheme 1 Classes of fluorescent boron chelates.

We recently disclosed that 1,5-benzodiazepin-2-ones were emissive in the aggregated and solid-state through the excited-state intramolecular proton transfer (ESIPT) photochemical process.¹⁴ In contrast, no fluorescence was observed in organic solvents in which this family of compounds was perfectly soluble. In fact, in solution state, the fluorescence of 1,5-benzodiazepin-2-ones is quenched by intramolecular motions that disrupt the intramolecular hydrogen bonding between the phenolic-OH and the imine nitrogen which was responsible for the ESIPT mechanism. From these results, it could be anticipated that complexation of 1,5-benzodiazepin-2-ones to boron difluoride via a phenoxy-imine chelate, would prevent the free rotation of the phenol ring during the deexcitation process, thus resulting in substantial modifications of their photophysical behaviours in solution. Accordingly, herein is reported the synthesis, and photophysical behaviour of a range of new 2-(2′-hydroxyphenyl)-1,5-benzodiazepin-2-one (HBD) borate complexes.

2. Results and discussion

HBD borate complexes were obtained within three steps from commercially available 4-hydroxycoumarin and 1,2-phenylenediamine derivatives. First, as recently reported,¹⁴ the imination/aminolysis sequence between 4-hydroxycoumarins and 1,2-phenylenediamines afforded the desired 2-(2′-hydroxyphenyl)-1,5-benzodiazepin-2-ones as a regioisomeric mixture (Scheme 2). The two isomers, substituted either at position 7 (= R²) or 8 (= R³) of the phenyl ring, were readily separable by column chromatography, except for the methyl and methoxy derivatives, which were isolated as an inseparable mixture, and used as such for the subsequent step. Then, the chemoselective N-methylation or N-propargylation of the amide moiety of 1,5-benzodiazepin-2-ones was achieved by means of NaH and methyl iodide or propargyl bromide in THF, affording the corresponding tertiary amides 2–11 in 74–93% yield. Finally, the boron complexation was achieved by treating benzodiazepin-2-ones with NaH followed by BF₃. Et₂O, to provide the corresponding complexes 12–22 in excellent 79–94% yield. HBD borate complexes were subsequently fully characterized by means of NMR, IR spectroscopy, and HRMS. First, evidence of the chelation of BF₂ by 1,5-benzodiazepin-2-ones was supported by ¹H NMR analysis which showed complete disappearance of the downfield proton signal around 14 ppm corresponding to the hydroxyl group. Furthermore, IR spectra revealed strong vibrations in 1000–1200 cm⁻¹ region indicating the presence of B–F bonds, as well as the disappearance of the broad absorption band at 3318 cm⁻¹ characteristic of a hydroxyl vibration. For compound 13, the chelate structure was further confirmed by crystallographic data, which displayed a six-membered ring system containing oxygen–boron–nitrogen linkages (Fig. 1). Crystals for X-ray analysis were obtained by slow evaporation of a DCM/Et₂O (2 : 3) solution of 13 at room temperature. On the ellipsoid representation (Fig. 1(a)), the fluorine atoms presented a disorder distribution on two crystallographic sites with 73/27% of statistical occupancy. Furthermore, it also appeared that the B₁–O₂ and B₁–N₁ bond lengths were 1.43 Å and 1.60 Å respectively, which was in agreement with those reported for analogous six-membered ring BF₂ complexes.¹⁵ Although the imine moiety was slightly out of the phenol plane, the dihedral angle (−14°) was apparently small enough to enable the delocalization of π-electrons within the system, thus causing fluorescence. An examination of the supramolecular structure of compound 13 revealed the presence of π–π interactions between phenol rings of two adjacent molecules (dashed blue lines), as well as C–H⋯F–B interactions (dashed pink lines), these dimeric interactions playing an important role in the cohesion of the crystal.

Scheme 2 Preparation of HBD borate complexes.

Fig. 1 Crystal structure of compound 13: (a) thermal ellipsoid representation (50% of probability); (b) dimeric interactions between adjacent molecules: π–π (dash blue lines), and C–H⋯F–B (dash pink lines) interactions.

Next, the spectroscopic behaviour of this series of compounds was determined, and collected in Table 1. Satisfyingly, unlike their phenol precursors,¹⁴ HBD complexes were not only emissive in the solid state but also in solution in organic media such as CHCl₃, THF or MeCN, in which they were perfectly soluble (Fig. 2). In fact, as one might expect, stiffening of the 1,5-benzodiazepin-2-one framework upon complexation to boron difluoride prevented intramolecular rotations and vibrations, favouring thus the radiative deexcitation pathway in solution.

Table 1 Spectral properties of HBD borate complexes

Cmpd	Matrix	λabs (nm)	λem (nm)	Stokes' shift (cm^−1)	ΦF
a Quantum yield determined at 25 °C by the relative method using anthracene (ΦF = 0.26 in EtOH) with excitation at 366 nm.b Absolute quantum yield determined at 25 °C by integrating sphere.
12	CHCl3^a	370	458	5192	0.10
	THF^a	370	458	5192	0.08
	MeCN^a	366	458	5488	0.07
	Solid^b		462		0.07
13	CHCl3	373	458	4975	0.14
	THF	369	458	5266	0.15
	MeCN	365	458	5563	0.09
	Solid		446		0.14
14	CHCl3	373	458	4975	0.10
	THF	368	459	5387	0.13
	MeCN	364	458	5638	0.11
	Solid		525		0.11
15a/b	CHCl3	375	458	4832	0.11
	THF	372	456	4951	0.10
	MeCN	367	456	5318	0.03
	Solid		466		0.06
16a/b	CHCl3	382	510	6570	0.05
	THF	361	508	8015	0.03
	MeCN	364	510	7864	<0.01
	Solid		571		0.30
17a	CHCl3	368	461	5481	0.09
	THF	369	461	5408	0.10
	MeCN	367	460	5508	0.10
	Solid		520		<0.01
17b	CHCl3	366	466	5863	0.15
	THF	372	465	5422	0.17
	MeCN	365	464	5845	0.16
	Solid		564		0.04
18a	CHCl3	374	456	5186	0.12
	THF	370	457	5145	0.11
	MeCN	364	458	5638	0.11
	Solid		527		0.08
18b	CHCl3	378	456	4525	0.17
	THF	370	457	5145	0.19
	MeCN	368	458	5339	0.17
	Solid		508		0.08
19a	CHCl3	377	459	4738	0.12
	THF	368	459	5387	0.12
	MeCN	366	459	5535	0.14
	Solid		566		0.14
19b	CHCl3	377	458	4691	0.18
	THF	368	458	5339	0.21
	MeCN	368	459	5387	0.16
	Solid		496		0.09
20a	CHCl3	384	490	5633	0.02
	THF	374	488	6246	0.05
	MeCN	370	494	6784	<0.01
	Solid		596		0.05
20b	CHCl3	377	468	5157	0.10
	THF	356	471	6858	0.11
	MeCN	360	472	6591	0.04
	Solid		583		0.01
21	CHCl3	356	426	4615	0.21
	THF	352	426	4934	0.22
	MeCN	350	426	5097	0.19
	PBS	350	426	5097	0.10
	Solid		510		0.04
22	CHCl3	362	428	4259	0.23
	THF	363	428	4183	0.24
	MeCN	360	428	4413	0.20
	PBS	360	430	4521	0.11
23	CHCl3	365	468	6029	0.28
	THF	356	471	6722	0.28
	MeCN	363	472	6361	0.23

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Fig. 2 Normalized absorption (blue), emission (red, λ_ex = 350 nm), excitation (green, λ_em = 458 nm) spectra for compound 2 in CHCl₃, at 25 °C.

While absorption maximum wavelengths were slightly affected by the solvent polarity (hypsochromic shift), no noticeable solvatofluorochromism was, however, observed. On the other hand, taken together, this family of compounds exhibited absorption and emission maxima in solution in the range of 350–384 nm and 426–494 nm, respectively, with large Stokes' shifts (4615–6858 cm⁻¹). First, comparing compound 12 with 13, it appeared that N-alkylation of the amide moiety tended to improve the quantum efficiency of the benzodiazepin-2-one derivative both in solution and solid-state. Next, the introduction of a halogen atom such as a chlorine, or a fluorine atom selectively at position 8 on the phenyl moiety of the fused ring system, noticeably increased the quantum yield up to 0.21. In contrast, any modification at position 7 resulted in the decrease of fluorescence intensity. In addition, modification with a nitro substituent caused a ∼30 nm bathochromic shift of the emission wavelength maxima in comparison to the unsubstituted analogue 13, and induced a remarkably large Stokes' shift (up to 6858 cm⁻¹). Regarding solid-state fluorescence of HBD complexes, it is worth noting that large bathochromic shifts were observed from the solution to the solid-state (up to 115 nm for compound 20b). In contrast with results obtained in solution, methoxy substituent increased or decreased the fluorescence intensity depending whether it is positioned on the phenol or on the fused ring system, respectively (0.30 and 0.04 for compounds 16a/b and 21, respectively).

Whilst compound 13 is stable in organic media, somewhat rapid decomplexation of the boron center was however observed in protic solvents such as ethanol or PBS (Fig. 3). In order to circumvent this shortcoming, the increase of the chelating ability of benzodiazepinone ligands toward boron difluoride was investigated by adding an electron-donating methoxy substituent on the phenol ring in para position of the imine moiety (compound 21, Table 1). Gratifyingly, this simple structural modification resulted in a marked increase in stability both in PBS and EtOH, without altering important properties of the benzodiazepin-2-one. Indeed the quantum yields were found to be in the range of 0.19–0.22 in organic solvents and 0.10 in PBS.

Fig. 3 Time-dependent fluorescence intensity of compounds 13 (black line: in PBS; grey line: in EtOH), and compound 21 (red line: in PBS; orange line: in EtOH) at 25 °C, at λ_ex = 0.350 nm, and λ_em = 458 nm.

Click chemistry¹⁶ and related chemical ligation processes¹⁷ have become an ubiquitous tool in diverse fields of research for the construction of (bio)molecular systems with a desired profile of properties. Accordingly, the compatibility of HBD complexes with click chemistry was then explored using compound 22, which bears a propargyl functional handle, as reaction partner with benzyl azide. Thus, treatment of 22 with benzyl azide in the presence of CuI (5 mol%) in DCM at room temperature afforded the corresponding triazole derivative 23 in 86% yield. Importantly, subsequent photophysical characterization revealed that quantum yields were high in all solvents tested (0.23–0.28) (Scheme 3).

Scheme 3 Compatibility study with click chemistry.

3. Conclusions

In conclusion, we reported the synthesis of a new family of 15 members of cyclic boranils based on the benzodiazepine scaffold. Subsequent investigation of their optical properties showed that most of them were fluorescent both in solution and solid-state, the vanishing of fluorescence being however specifically observed in solution with the presence of the methoxy substituent on the fused-aromatic ring system. On the other hand, this methoxy group proved highly valuable in terms of hydrolytic stability and quantum yield when positioned on the phenol ring. This promising result suggests that there is room for further improvements so as to use them eventually in bioimaging applications.

4. Experimental

All solvents were dried following standard procedures: toluene, methylene chloride (DCM) were obtained from MB SPS-800 apparatus from MBRAUN. THF: distillation over Na°/benzophenone. Cyclohexane and ethyl acetate (EtOAc) were purchased at ACS grade quality and used without further purification. Commercially available reagents were used without further purification, unless otherwise stated. All reactions involving air and moisture sensitive reagents were performed under argon using syringe-septum cap technique. Column chromatography purifications were performed on silica gel (40–63 μm) carried out on Merck DC Kieselgel 60. Thin-layer chromatography (TLC) analyses were carried out on Merck DC Kieselgel 60 F-254 aluminum sheets. The spots were visualized through illumination with UV lamp (λ = 254 nm) and/or staining with KMnO₄. Phosphate buffered saline (PBS, 10 mM phosphate + 15 mM NaCl, pH 7.4), aq. 0.1 M and 1.0 M sodium acetate buffer were prepared using water purified with a Milli-Q system (purified to 18.2 MΩ cm).

4.1. Instruments and methods

IR spectra were recorded with a universal ATR sampling accessory. ¹H and ¹³C NMR spectra (C13APT or C13CPD experiments) were recorded on a 300 MHz spectrometer. Chemical shifts are expressed in parts per million (ppm) from the residual non-deuterated solvent signal: [D6]DMSO (δ_H = 2.50, δ_C = 39.52), multiplicities are described as s (singlet), d (doublet), dd, ddd, etc. (doublet of doublets, doublet of doublets of doublets, etc.), t (triplet), dt (doublet of triplets), td (triplet of doublets), m (multiplet), bs (broad singlet). Coupling constants, J values, are reported in Hz. High-resolution mass spectra (HRMS) were obtained using an orthogonal acceleration time-of-flight (oa-TOF) mass spectrometer equipped with an electrospray source and in the positive and negative modes (ESI±). UV-visible spectra were obtained using a rectangular quartz cell (Open Top, 10 × 10 mm, 3.5 mL). Solid-state fluorescence quantum yields were determined using an integrating sphere instrument (F-3018 Horiba–Jobin–Yvon or G8 GMP) according to a reported method.¹⁸ Fluorescence spectroscopic studies in solution were performed with a semi-micro quartz fluorescence cell (Hellma, 104F-QS, light patch base thickness 10 × 4 mm, chamber volume: 1400 μL), with excitation and emission slit widths of 5 nm. Solvents for spectroscopy were spectroscopic grade. Fluorescence quantum yields in 0.1 M PBS pH 7.4 were measured at 25 °C by a relative method using anthracene (Φ_F = 0.26 in ethanol)¹⁹ as a standard. The following equation was used to determine the relative fluorescence quantum yield in solution:

Φ_F(x) = (A_s/A_x)(F_x/F_s)(n_x/n_s)²Φ_F(s)

where A is the absorbance (in the range of 0.01–0.1 A.U.), F is the area under the emission curve, n is the refractive index of the solvents (at 25 °C) used in measurements, and the subscripts s and x represent standard and unknown, respectively. The following refractive index values were used: 1.333 for aq. H₂SO₄, and 1.337 for PBS.

4.2. Syntheses

4.2.1. Imination/aminolysis sequence: construction of the benzodiazepin-2-one scaffold. The synthesis of most of these derivatives was already reported,¹⁴ except those reported below.
4-(2-Hydroxyphenyl)-7-methoxy-1,5-benzodiazepin-2-one and 4-(2-hydroxyphenyl)-8-methoxy-1,5-benzodiazepin-2-one. A solution of 4-hydroxycoumarin (1.62 g, 10 mmol) and 4-methoxy-1,2-phenylenediamine (1.08 g, 10 mmol, 1 equiv.) in acetic acid/ethanol (40 mL, 1 : 1, v/v) was refluxed for 3 h. Then, the reaction mixture was cooled to room temperature, filtered, and the precipitate washed with methanol several times and purified by chromatography on silica gel as a yellow solid as an inseparable mixture of regioisomers in a 0.09 : 1 ratio (2.05 g, 72% yield) as a yellow solid, mp = 396–298 °C. IR (ATR): ν_max: 3150 (NH), 3100 (OH) 1668 (CN), 1595 (CO). ¹H NMR (300 MHz, [D6]DMSO): δ = 3.33 (s, 2.25H), 3.81 (s, 3.35H), 6.93–7.02 (m, 4.47H), 7.17 (d, J = 9 Hz, 1.07H), 7.44–7.50 (m, 1.14H), 7.91 (d, J = 9 Hz, 1.07H), 10.55 (s, 1H), 10.66 (s, 0.09H), 14 (s, 1H), 14.18 (s, 0.09H) ppm. ¹³C NMR (75 MHz, [D6]DMSO): δ = 38.6, 55.5, 109.9, 115, 117.6, 118.1, 118.9, 123.2, 124.7, 129.7, 137.2, 155.9, 161.4, 163, 165.6 ppm. HRMS (ESI+): calcd for C₁₆H₁₄N₂O₃ [M + H]⁺ 282.1083; found 282.1091.
4-(2-Hydroxy-4-methoxyphenyl)-1,5-benzodiazepin-2-one. A solution of 7-methoxy-4-hydroxycoumarin (96 mg, 5 mmol) and 1,2-phenylenediamine (54 mg, 5 mmol, 1 equiv.) in p-xylene (25 mL) was refluxed for 3 h. Then, the reaction mixture was cooled to room temperature, filtered, and the precipitate washed with methanol several times to afford the corresponding compound (1.08 g, 3.82 mmol, 77% yield) as a yellow solid, mp = 288–290 °C. IR (ATR): ν_max: 3150 (NH), 3100 (OH) 1673 (CN), 1621 (CO). ¹H NMR (300 MHz, [D6]DMSO): δ = 3.56 (s, 2H), 3.81 (s, 3H), 6.51–6.91 (m, 2H), 7.21–7.43 (m, 4H), 7.84 (d, J = 9 Hz, 1H), 10.68 (s, 1H), 14.65 (s, 1H) ppm. ¹³C NMR (75 MHz, [D6]DMSO): δ = 38.4, 55.5, 101.4, 106.7, 111.5, 122.1, 124.5, 126.7, 127.1, 131.1, 131.2, 136.2, 162.7, 163.9, 164, 166 ppm. HRMS (ESI+): calcd for C₁₆H₁₅N₂O₃ [M + H]⁺ 282.1083; found 282.1091.

4.2.2. N-Methylation: synthesis of benzodiazepin-2-ones 4–10.
General procedure. To a solution of the appropriate 4-phenyl-1,3-dihydro-1,5-benzodiazepin-2-one derivative (1 mmol) in anhydrous THF (20 mL) at 0° C, was added NaH (60% in mineral oil, 0.044 g, 1.1 mmol, 1.1 equiv.). The mixture was stirred for 10 to 15 min before the addition of methyl iodide (0.124 mL, 2 mmol, 2 equiv.). The reaction mixture was maintained at room temperature for 2 h, before removing the solvent under reduced pressure. The crude material was purified by flash column chromatography on silica gel (cyclohexane/EtOAc from 100 : 0 to 80 : 20) to obtain the desired product.
Mixture of 4-(2-hydroxyphenyl)-(1,7)-dimethyl-1,5-benzodiazepin-2-one 4a and 4-(2-hydroxyphenyl)-(1,8)-dimethyl-1,5-benzodiazepin-2-one 4b. (210 mg, 0.75 mmol), 75% yield, isolated as a yellow solid and as an inseparable mixture of regioisomers 4a/4b in a 0.56 : 1 ratio, mp = 80–82 °C. IR (ATR): ν_max: 2989 (OH), 2915 (OH), 1667 (CN), 1591 (CO). ¹H NMR (300 MHz, [D6]DMSO): δ = 2.37 (s, 3H), 2.40 (s, 1.7H), 3.04 (d, J = 12 Hz, 1.29H), 3.29 (s, 3H), 3.31 (s, 1.79H), 4.27 (d, J = 12 Hz, 1.28H), 6.9–7.03 (m, 2.80H), 7.15–7.27 (m, 2.79H), 7.34–7.50 (m, 3.62H), 7.92–7.94 (m, 1.36), 14 (s, 1H), 14.01 (s, 0.39H) ppm. ¹³C NMR (75 MHz, [D6]DMSO): δ = 20.1, 20.7, 34.7, 34.8, 37.9, 117.6, 117.6, 117.8, 118.9, 122.2, 122.5, 126.2, 126.4, 128.1, 129.8, 129.8, 133.4, 133.9, 134, 134.8, 135.4, 135.5, 137, 137.4, 161.3, 161.4, 164, 164.5, 165.1, 165.1 ppm. HRMS (ESI+): calcd for C₁₇H₁₆N₂O₂ [M + H]⁺ 281.1290; found 281.1280.
Mixture of 4-(2-hydroxyphenyl)-7-methoxy-1-methyl-1,5-benzodiazepin-2-one 5a and 4-(2-hydroxyphenyl)-8-methoxy-1-methyl-1,5-benzodiazepin-2-one 5b. (263 mg, 0.89 mmol), 89% yield, isolated as a yellow solid and as an inseparable mixture of regioisomers 5a/5b in a 0.09 : 1 ratio, mp = 142–144 °C. IR (ATR): ν_max: 3020 (OH), 1657 (CN), 1593 (CO). ¹H NMR (300 MHz, [D6]DMSO): δ = 3.06 (d, J = 12 Hz, 1.06H), 3.28 (s, 3H), 3.32 (s, 0.25H), 3.83 (s, 3H), 3.85 (s, 0.25H), 4.27 (d, J = 12 Hz, 1.06H), 6.94–7.08 (m, 4.53H), 7.39–7.59 (m, 2.28H), 7.92–7.95 (m, 1.1H), 13.88 (s, 1H), 14.04 (s, 0.07H) ppm. ¹³C NMR (75 MHz, [D6]DMSO): δ = 34.8, 38, 55.6, 109.4, 114.7, 117.6, 117.8, 119, 123.6, 129.3, 130, 134.1, 138.7, 156.2, 161.3, 164.8, 165 ppm. HRMS (ESI+): calcd for C₁₇H₁₆N₂O₃ [M]⁺ 296.1160; found 296.1153.
4-(2-Hydroxyphenyl)-7-bromo-1-methyl-1,5-benzodiazepin-2-one 6a. (282 mg, 0.82 mmol), 82%, isolated as a yellow solid, mp = 158–160 °C. IR (ATR): ν_max: 3010 (OH), 1671 (CN), 1595 (CO). ¹H NMR (300 MHz, [D6]DMSO): δ = 3.11 (d, J = 12 Hz, 1H), 3.31 (s, 3H), 4.31 (d, J = 12 Hz, 1H), 6.97–7.02 (m, 2H), 7.40–7.52 (m, 3H), 7.79 (m, 1H), 7.93 (d, J = 9 Hz, 1H), 13.65 (s, 1H) ppm. ¹³C NMR (75 MHz, [D6]DMSO): δ = 34.8, 38.1, 117.6, 117.9, 119.1, 119.2, 125.1, 128.1, 128.5, 130, 134.2, 137, 137.1, 161.2, 165.1, 165.2 ppm. HRMS (ESI+): calcd for C₁₆H₁₃BrN₂O₂ [M]⁺ 344.0160; found 344.0169.
4-(2-Hydroxyphenyl)-8-bromo-1-methyl-1,5-benzodiazepin-2-one 6b. (313 mg, 0.91 mmol, 91%), isolated as a yellow solid, mp = 162–164 °C. IR (ATR): ν_max: 3000 (OH), 1669 (CN), 1595 (CO). ¹H NMR (300 MHz, [D6]DMSO): δ = 3.11 (d, J = 12 Hz, 1H), 3.29 (s, 3H), 4.31 (d, J = 12 Hz, 1H), 6.97–7.02 (m, 2H), 7.45–7.56 (m, 3H), 7.70 (d, J = 3 Hz, 1H), 7.94 (d, J = 9 Hz, 1H), 13.49 (s, 1H) ppm. ¹³C NMR (75 MHz, [D6]DMSO): δ = 34.7, 38.2, 117, 117.7, 117.8, 119.1, 124.5, 128.7, 129.6, 130.1, 134.3, 135.1, 139.2, 161.2, 165.1, 165.7 ppm. HRMS (ESI+): calcd for C₁₆H₁₃BrN₂O₂ [M]⁺ 344.0173; found 344.0170.
4-(2-Hydroxyphenyl)-7-chloro-1-methyl-1,5-benzodiazepin-2-one 7a. (252 mg, 0.84 mmol, 84%), isolated as a yellow solid, mp = 170–172 °C. IR (ATR): ν_max: 3000 (OH), 1673 (CN), 1590 (CO). ¹H NMR (300 MHz, [D6]DMSO): δ = 3.12 (d, J = 12 Hz, 1H), 3.22 (s, 3H), 4.32 (d, J = 12 Hz, 1H), 6.98–7.03 (m, 2H), 7.37–7.52 (m, 3H), 7.69 (d, J = 3 Hz, 1H), 7.93–7.96 (dd, J = 6 Hz, J = 3 Hz, 1H), 13.67 (s, 1H) ppm. ¹³C NMR (75 MHz, [D6]DMSO): δ = 34.8, 36.1, 117.6, 117.8, 119.1, 122.3, 125.2, 127.4, 128.3, 130, 131, 134.2, 136.7, 161.2, 165.1, 165.2 ppm. HRMS (ESI+): calcd for C₁₆H₁₄ClN₂O₂ [M + H]⁺ 301.0744; found 301.0742.
4-(2-Hydroxyphenyl)-8-chloro-1-methyl-1,5-benzodiazepin-2-one 7b. (276 mg, 0.92 mmol, 92%), isolated as a yellow solid, mp = 145–147 °C. IR (ATR): ν_max: 2980 (OH), 1674 (CN), 1587 (CO). ¹H NMR (300 MHz, [D6]DMSO): δ = 3.12 (d, J = 12 Hz, 1H), 3.31 (s, 3H), 4.32 (d, J = 12 Hz, 1H), 7.01 (t, J = 9 Hz, 2H), 7.44–7.61 (m, 4H), 7.93–7.96 (dd, J = 9 Hz, J = 3 Hz, 1H), 13.50 (s, 1H) ppm. ¹³C NMR (75 MHz, [D6]DMSO): δ = 34.8, 38.2, 117.7, 117.8, 119.1, 124.3, 125.8, 126.8, 128.9, 130.1, 134.4, 134.7, 138.9, 161.2, 165.1, 165.7 ppm. HRMS (ESI+): calcd for C₁₆H₁₄ClN₂O₂ [M + H]⁺ 301.0744; found 301.0736.
4-(2-Hydroxyphenyl)-7-fluoro-1-methyl-1,5-benzodiazepin-2-one 8a. (230 mg, 0.81 mmol, 81%), isolated as a yellow solid, mp = 188–190 °C. IR (ATR): ν_max: 2990 (OH), 1673 (CN), 1594 (CO). ¹H NMR (300 MHz, [D6]DMSO): δ = 3.14 (sb, 1H), 3.32 (s, 3H), 4.30 (sb, 1H), 6.97–7.03 (m, 2H), 7.20–7.26 (m, 1H), 7.45–7.56 (m, 3H), 7.92–7.95 (dd, J = 9 Hz, J = 3 Hz, 1H), 13.76 (s, 1H) ppm. ¹³C NMR (75 MHz, [D6]DMSO): δ = 34.7, 37.9, 109, 109.4, 112.6, 112.9, 117.6, 117.8, 119, 128.5, 128.6, 129.9, 134, 134.6, 134.6, 136.8, 136.9, 158.5, 161.2, 161.8, 164.4, 165.1 ppm. HRMS (ESI+): calcd for C₁₆H₁₃FN₂O₂ [M + H]⁺ 285.1039; found 285.1031.
4-(2-Hydroxyphenyl)-8-fluoro-1-methyl-1,5-benzodiazepin-2-one 8b. (264 mg, 0.93 mmol, 93%), isolated as a yellow solid, mp = 138–140 °C. IR (ATR): ν_max: 2976 (OH), 1667 (CN), 1593 (CO). ¹H NMR (300 MHz, [D6]DMSO): δ = 3.11 (d, J = 12 Hz, 1H), 3.20 (s, 3H), 3.31 (d, J = 12 Hz, 1H), 6.98–7.04 (m, 2H), 7.28–7.33 (m, 1H), 7.37–7.41 (dd, J = 9 Hz, J = 3 Hz, 1H), 7.46–7.52 (td, J = 9 Hz, J = 3 Hz, 1H), 7.59–7.64 (m, 1H), 7.93–7.96 (dd, J = 9 Hz, J = 3 Hz, 1H), 13.56 (s, 3H) ppm. ¹³C NMR (75 MHz, [D6]DMSO): δ = 34.9, 38.1, 122.2, 112.5, 114.2, 114.5, 117.6, 117.8, 119.1, 124.4, 124.5, 130.1, 132.4, 132.4, 134.3, 139, 139.1, 156.9, 160.1, 161.2, 165.1, 165.6 ppm. HRMS (ESI+): calcd for C₁₆H₁₃FN₂O₂ [M + H]⁺ 285.1039; found 285.1039.
4-(2-Hydroxyphenyl)-7-nitro-1-methyl-1,5-benzodiazepin-2-one 9a. (230 mg, 0.74 mmol, 74%), isolated as a yellow solid, mp = 205–207 °C. IR (ATR): ν_max: 2983 (OH), 1674 (CN), 1600 (CO). ¹H NMR (300 MHz, [D6]DMSO): δ = 3.20 (d, J = 12 Hz, 1H), 3.40 (s, 3H), 4.41 (d, J = 12 Hz, 1H), 7.03 (t, J = 6 Hz, 2H), 7.50–7.56 (td, J = 9 Hz, J = 3 Hz, 1H), 7.73 (d, J = 9 Hz, 1H), 7.88 (d, J = 6 Hz, 1H), 8.13–8.17 (dd, J = 9 Hz, J = 3 Hz, 1H), 8.37 (d, J = 3 Hz, 1H), 13.29 (s, 1H) ppm. ¹³C NMR (75 MHz, [D6]DMSO): δ = 34.8, 38.6, 117.7, 117.9, 118.4, 119.3, 119.7, 128, 130.4, 134.9, 136, 142.9, 145.1, 161.3, 165.3, 167 ppm. HRMS (ESI+): calcd for C₁₆H₁₄N₃O₄ [M + H]⁺ 312.0984; found 312.0979.
4-(2-Hydroxyphenyl)-8-nitro-1-methyl-1,5-benzodiazepin-2-one 9b. (248 mg, 0.80 mmol, 80%), isolated as a yellow solid, mp = 188–190 °C. IR (ATR): ν_max: 2983 (OH), 1688 (CN), 1617 (CO). ¹H NMR (300 MHz, [D6]DMSO): δ = 3.22 (sb, 1H), 3.40 (s, 3H), 4.41 (sb, 1H), 7.02 (t, J = 6 Hz, 2H), 7.51 (t, J = 6 Hz, 1H), 7.78 (d, J = 9 Hz, 1H), 7.97 (d, J = 6 Hz, 1H), 8.20–8.24 (dd, J = 9 Hz, J = 3 Hz, 1H), 8.33 (d, J = 3 Hz, 1H), 13.23 (s, 1H) ppm. ¹³C NMR (75 MHz, [D6]DMSO): δ = 35, 38.5, 117.7, 117.9, 119.2, 121.2, 122.3, 123.8, 130.3, 134.6, 138, 140.9, 143.6, 161.1, 165.2, 166.4 ppm. HRMS (ESI+): calcd for C₁₆H₁₄N₃O₄ [M + H]⁺ 312.0984; found 312.0971.
4-(2-Hydroxy-4-methoxyphenyl)-1-methyl-1,5-benzodiazepin-2-one 10. (0.248 g, 0.84 mmol, 84% yield) was obtained as yellow solid, mp = 158–160 °C. IR (ATR): ν_max: 3050 (OH) 1658 (CN), 1619 (CO). ¹H NMR (300 MHz, [D6]DMSO): δ = 3.02 (d, J = 12 Hz, 1H), 3.33 (s, 3H), 3.81 (s, 3H), 4.21 (d, J = 12 Hz), 6.51–6.60 (m, 2H), 7.29–7.56 (m, 4H), 7.86 (d, J = 9 Hz, 1H), 14.47 (s, 1H) ppm. ¹³C NMR (75 MHz, [D6]DMSO): δ = 34.8, 37.8, 55.5, 101.4, 106.7, 111.3, 122.5, 125.3, 126.4, 126.7, 131.4, 135.7, 137.7, 163.9, 164.1164.3, 165.3 ppm. HRMS (ESI+): calcd for C₁₇H₁₇N₂O₃ [M + H]⁺ 297.1239; found 297.1236.

4.2.3. N-Propargylation: synthesis of benzodiazepin-2-ones 3 and 11.
General procedure. To a solution of the appropriate 4-phenyl-1,3-dihydro-1,5-benzodiazepin-2-one derivative (1 mmol) in anhydrous THF (20 mL) at 0° C, was added NaH (60% in mineral oil, 0.044 g, 1.1 mmol, 1.1 equiv.). The mixture was stirred for 10 to 15 min before the addition propargyl bromide (0.122 mL, 1.1 mmol, 1.1 equiv.). The reaction mixture was maintained at 60 °C for 4 h, before removing the solvent under reduced pressure. The crude material was purified by flash column chromatography on silica gel (cyclohexane/EtOAc from 100 : 0 to 80 : 20) to obtain the desired product.
4-(2-Hydroxyphenyl)-1-(prop-2-yn-1-yl)-1,5-benzodiazepin-2-one 3. (249 mg, 0.86 mmol, 86%) was obtained as a yellow solid, mp = 143–145 °C. IR (ATR): ν_max: 3227 (CH), 2983 (OH), 1683 (CN), 1593 (CO). ¹H NMR (300 MHz, [D6]DMSO): δ = 3.14 (d, J = 15 Hz, 1H), 3.24 (t, J = 3 Hz, 1H), 3.36 (d, J = 15 Hz, 1H), 4.64–4.67 (dd, J = 6 Hz, J = 3 Hz, 2H), 6.98–7.05 (m, 2H), 7.36–7.51 (m, 4H), 7.74–7.77 (m, 1H), 7.94–7.97 (dd, J = 9 Hz, J = 3 Hz, 1H), 13.86 (s, 1H) ppm. ¹³C NMR (75 MHz, [D6]DMSO): δ = 36.4, 37.8, 74.8, 79.5, 117.6, 117.8, 119, 122.2, 125.9, 126.8, 127.3, 130, 133.9, 134.2, 138.2, 161.3, 164.6, 164.8 ppm. HRMS (ESI+): calcd for C₁₈H₁₅N₂O₂ [M + H]⁺ 291.1123; found 291.1122.
4-(2-Hydroxy-4-methoxyphenyl)-1-(prop-2-yn-1-yl)-1,5-benzodiazepin-2-one 11. (0.243 g, 0.76 mmol, 76% yield) was obtained as a yellow solid, mp = 148–150 °C. IR (ATR): ν_max: 3200 (CH), 3000 (OH), 1685 (CN), 1610 (CO). ¹H NMR (300 MHz, [D6]DMSO): δ = 3.09 (d, J = 15 Hz, 1H), 3.23 (t, J = 3 Hz, 1H), 3.82 (s, 3H), 4.27 (d, J = 15 Hz, 1H), 4.62–4.65 (dd, J = 9 Hz, J = 3 Hz, 2H), 6.52 (d, J = 3 Hz, 1H), 6.58–6.62 (dd, J = 9 Hz, J = 3 Hz, 1H), 7.36–7.45 (m, 3H), 7.71–7.74 (m, 1H), 7.87 (d, J = 9 Hz, 1H), 14.40 (s, 1H) ppm. ¹³C NMR (75 MHz, [D6]DMSO): δ = 36.4, 37.7, 55.5, 74.8, 79.6, 101.4, 106.8, 111.3, 122.2, 125.9, 126.6, 126.8, 131.5, 133.9, 138.2, 163.9, 164.1, 164.3, 164.7 ppm. HRMS (ESI+): calcd for C₁₉H₁₇N₂O₃ [M + H]⁺ 321.1239; found 321.1238.

4.2.4. Complexation: synthesis of HBD complexes 12–22.
General procedure. To a solution the appropriate 4-(2′-hydroxyphenyl)-1,5-benzodiazepin-2-one derivative (0.5 mmol) in anhydrous THF (5 mL) at room temperature, was added NaH (60% in mineral oil, 22 mg, 0.55 mmol, 1.1 equiv.). The mixture was stirred for 10 to 15 min before the addition of boron trifluoride diethyl etherate (75 μL, 0.6 mmol, 1.2 equiv.). The reaction mixture was maintained at room temperature for 15–20 min. The crude reaction was filtered through Celite® before removing the solvent under reduced pressure. The crude material was recrystallized from diethyl ether.
4-(2-((Difluoroboranyl)oxy)phenyl)-1,5-benzodiazepin-2-one 12. (125 mg, 0.42 mmol, 83%), isolated as a white solid, mp = 288–290 °C. IR (ATR): ν_max: 922 (BN), 1060 (BF), 1120 (BF), 3215 (NH), 1698 (CN), 1651 (CO). ¹H NMR (300 MHz, [D6]DMSO): δ = 3.42 (d, J = 15 Hz, 1H), 4.50 (d, J = 15 Hz, 1H), 7.14–7.22 (m, 2H), 7.33–7.42 (m, 2H), 7.53–7.59 (td, J = 6 Hz, J = 3 Hz, 1H), 7.76–7.86 (m, 2H), 8.24–8.27 (dd, J = 6 Hz, J = 3 Hz, 1H), 11.0 (s, 1H) ppm. ¹³C NMR (75 MHz, [D6]DMSO): δ = 38.7, 115.4, 119.3, 120.9, 122.6, 124.6, 126.4, 129.7, 131.2, 131.3, 133.9, 138.9, 158.5, 158.6, 165.9, 166.3 ppm. HRMS (ESI−): calcd for C₁₅H₁₀BF₂N₂O₂ [M − H]⁻ 299.0803; found 299.0803.
4-(2-((Difluoroboranyl)oxy)phenyl)-1-methyl-1,5-benzodiazepin-2-one 13. (146 mg, 0.46 mmol, 93%), isolated as a white solid, mp = 233–235 °C. IR (ATR): ν_max: 916 (BN), 1070 (BF), 1103 (BF), 1677 (CN), 1599 (CO). ¹H NMR (300 MHz, [D6]DMSO): δ = 3.31 (s, 3H), 3.46 (d, J = 12 Hz, 1H), 4.56 (d, J = 12 Hz, 1H), 7.13–7.22 (m, 2H), 7.44–7.49 (td, J = 6 Hz, J = 3 Hz, 1H), 7.61–7.89 (m, 4H) ppm. ¹³C NMR (75 MHz, [D6]DMSO): δ = 34.7, 38.3, 115.2, 119.4, 120.9, 122.8, 125.5, 125.9, 129.9, 131.4, 132.2, 138, 139.1, 158.6, 158.6, 165.3, 167 ppm. HRMS (ESI−): calcd for C₁₆H₁₄BF₂N₂O₂ [M − H]⁻ 313.0970; found 313.0960.
4-(2-((Difluoroboranyl)oxy)phenyl)-1-(prop-2-yn-1-yl)-1,5-benzodiazepin-2-one 14. (145 mg, 0.43 mmol, 86%), isolated as a light green solid, mp = 238–240 °C. IR (ATR): ν_max: 918 (BN), 1055 (BF), 1142 (BF), 3249 (CH), 1675 (CN), 1612 (CO). ¹H NMR (300 MHz, [D6]DMSO): δ = 3.28 (t, J = 3 Hz, 3H), 3.55 (d, J = 12 Hz, 1H), 4.62 (d, J = 12 Hz, 1H), 4.67 (d, J = 3 Hz, 2H), 7.14–7.24 (m, 2H), 7.48–7.54 (td, J = 9 Hz, J = 3 Hz, 1H), 7.65–7.71 (td, J = 9 Hz, J = 3 Hz, 1H), 7.77–7.89 (m, 3H), 7.26–7.29 (dd, J = 9 Hz, J = 3 Hz, 1H) ppm. ¹³C NMR (75 MHz, [D6]DMSO): δ = 36.3, 38.2, 75.3, 78.8, 115.2, 119.4, 121, 122.7, 126.1, 129.9, 131.4, 132.8, 136.2, 139.2, 158.6, 158.7, 164.6, 167.1 ppm. HRMS (ESI−): calcd for C₁₈H₁₂BF₂N₂O₂ [M − H]⁻ 337.0960; found 337.0967.
4-(2-((Difluoroboranyl)oxy)phenyl)-(1,7)dimethyl-1,5-benzodiazepin-2-one 15a and 4-(2-((difluoroboranyl)oxy)phenyl)-(1,8)dimethyl-1,5-benzodiazepin-2-one 15b. (142 mg, 0.43 mmol, 87%), isolated as a white solid, and as an inseparable mixture of regioisomers 15a/15b in a 0.56 : 1 ratio, mp = 258–260 °C. IR (ATR): ν_max: 970 (BN), 1120 (BF), 1148 (BF), 1602 (CO), 1681 (CN). ¹H NMR (300 MHz, [D6]DMSO): δ = 2.42 (s, 3H), 2.45 (s, 0.91H), 3.29 (s, 3H), 3.31 (s, 0.91H), 3.44 (d, J = 12 Hz, 1.3H), 4.55 (d, J = 12 Hz, 1.3H), 7.13–7.30 (m, 2.9H), 7.44–7.64 (m, 3.44H), 7.46–7.81 (m, 1.57H), 8.24–8.27 (dd, J = 9 Hz, J = 3 Hz, 1.3H) ppm. ¹³C NMR (75 MHz, [D6]DMSO): δ = 20.5, 20.8, 34.6, 38.3, 115.2, 119.3, 120.9, 122.6, 122.7, 125.6, 126.4, 130.7, 131.3, 131.4, 132, 135, 135.8, 138.9, 139, 140.1, 158.5, 158.6, 165.1, 165.2, 166.7 ppm. HRMS (ESI−): calcd for C₁₇H₁₄BF₂N₂O₂ [M − H] 327.1116; found 327.1123.
4-(2-((Difluoroboranyl)oxy)phenyl)-7-methoxy-1-methyl-1,5-benzodiazepin-2-one 16a and 4-(2-((difluoroboranyl)oxy)phenyl)-7-methoxy-1-methyl-1,5-benzodiazepin-2-one 16b. (161 mg, 0.47 mmol, 94%), isolated as a white solid and as an inseparable mixture of regioisomers 16a/16b in a 0.09 : 1 ratio mp = 208–210 °C. IR (ATR): ν_max: 950 (BN), 1051 (BF), 1148 (BF), 1602 (CO), 1680 (CN). ¹H NMR (300 MHz, [D6]DMSO): δ = 3.28 (s, 3H), 3.32 (s, 0.27H), 3.46 (d, J = 12 Hz, 1.1H), 3.84 (s, 3H), 3.89 (s, 0.28H), 4.55 (d, J = 12 Hz, 1.09H), 7.13–7.31 (m, 4.49H), 7.6–7.63 (m, 1.05H), 7.79 (t, J = 9 Hz, 1.18H), 8.25 (d, J = 9 Hz, 1.07H) ppm. ¹³C NMR (75 MHz, [D6]DMSO): δ = 34.7, 38.4, 55.7, 109.9, 109.9, 110, 115.1, 116.4, 116.4, 121, 124, 131.4, 131.8, 133, 139.2, 155.8, 158.6, 158.6, 165, 167, 1 ppm. HRMS (ESI+): calcd for C₁₇H₁₅BF₂N₂O₃ [M]⁺ 344.1143; found 344.1156.
4-(2-((Difluoroboranyl)oxy)phenyl)-7-bromo-1-methyl-1,5-benzodiazepin-2-one 17a. (176 mg, 0.45 mmol, 90%), isolated as a yellow solid, mp = 260–262 °C. IR (ATR): ν_max: 905 (BN), 1052 (BF), 1142 (BF), 1608 (CO), 1689 (CN). ¹H NMR (300 MHz, [D6]DMSO): δ = 3.32 (s, 3H), 3.56 (d, J = 12 Hz, 1H), 4.60 (d, J = 12 Hz, 1H), 7.13–7.23 (m, 2H), 7.67–7.93 (m, 4H), 8.27 (d, J = 9 Hz, 1H) ppm. ¹³C NMR (75 MHz, [D6]DMSO): δ = 34.8, 38.3, 115.2, 119.4, 121, 122.5, 125.6, 127.6, 128.5, 128.6, 131.5, 139.3, 139.4, 158.6, 158.4, 165.2, 167.3 ppm. HRMS (ESI+): calcd for C₁₆H₁₂BBrF₂N₂O₂ [M]⁺ 392.0143; found 392.0151.
4-(2-((Difluoroboranyl)oxy)phenyl)-8-bromo-1-methyl-1,5-benzodiazepin-2-one 17b. (186 mg, 0.47 mmol, 95%), isolated as a yellow solid, mp = 163–165 °C. IR (ATR): ν_max: 924 (BN), 1053 (BF), 1103 (BF), 1611 (CO), 1698 (CN). ¹H NMR (300 MHz, [D6]DMSO): δ = 3.30 (s, 3H), 3.56 (d, J = 12 Hz, 1H), 4.61 (d, J = 12 Hz, 1H), 7.15–7.24 (m, 2H), 7.64–7.94 (m, 4H), 8.29 (d, J = 6 Hz, 1H) ppm. ¹³C NMR (75 MHz, [D6]DMSO): δ = 34.7, 38.3, 115, 117, 119.4, 121.1, 125, 128.1, 128.2, 128.2, 131.6, 132.6, 133.2, 137.5, 139.6, 158.7, 158.8, 165, 167.9 ppm. HRMS (ESI+): calcd for C₁₆H₁₂BBrF₂N₂O₂ [M]⁺ 392.0143; found 392.0136.
4-(2-((Difluoroboranyl)oxy)phenyl)-7-chloro-1-methyl-1,5-benzodiazepin-2-one 18a. (158 mg, 0.45 mmol, 91%), isolated as a yellow solid, mp = 253–255 °C. IR (ATR): ν_max: 919 (BN), 1068 (BF), 1100 (BF), 1677 (CN), 1612 (CO). ¹H NMR (300 MHz, [D6]DMSO): δ = 3.32 (s, 3H), 3.56 (d, J = 12 Hz, 1H), 4.60 (d, J = 12 Hz, 1H), 7.13–7.23 (m, 2H), 7.54–7.58 (dd, J = 9 Hz, J = 3 Hz, 1H), 7.77–7.86 (m, 3H), 8.26–8.29 (dd, J = 9 Hz, J = 3 Hz, 1H) ppm. ¹³C NMR (75 MHz, [D6]DMSO): δ = 34.7, 38.3, 115.1, 119.4, 121, 122.8, 125.6, 127.6, 131.1, 131.5, 134, 139.2, 139.4, 158.6, 158.7, 165.1, 167.3 ppm. HRMS (ESI−): calcd for C₁₆H₁₁BClF₂N₂O₂ [M − H]⁻ 347.0570; found 347.0565.
4-(2-((Difluoroboranyl)oxy)phenyl)-8-chloro-1-methyl-1,5-benzodiazepin-2-one 18b. (161 mg, 0.46 mmol, 93%), isolated as a yellow solid, mp = 238–240 °C. IR (ATR): ν_max: 927 (BN), 1053 (BF), 1101 (BF), 1698 (CN), 1612 (CO). ¹H NMR (300 MHz, [D6]DMSO): δ = 3.31 (s, 3H), 3.57 (d, J = 12 Hz, 1H), 4.62 (d, J = 12 Hz, 1H), 7.15–7.64 (m, 2H), 7.73–7.83 (m, 4H), 8.28–8.31 (dd, J = 9 Hz, J = 3 Hz, 1H) ppm. ¹³C NMR (75 MHz, [D6]DMSO): δ = 34.7, 38.3, 115, 119.4, 121.1, 124.9, 125.3, 129, 129.7, 131.6, 133, 137.2, 139.6, 158.7, 158.8, 165, 167.9 ppm. HRMS (ESI−): calcd for C₁₆H₁₁BClF₂N₂O₂ [M − H]⁻ 347.0570; found 347.0573.
4-(2-((Difluoroboranyl)oxy)phenyl)-7-fluoro-1-methyl-1,5-benzodiazepin-2-one 19a. (146 mg, 0.44 mmol, 88%), isolated as a yellow solid, mp = 258–260 °C. IR (ATR): ν_max: 920 (BN), 1059 (BF), 1121 (BF), 1694 (CN), 1592 (CO). ¹H NMR (300 MHz, [D6]DMSO): δ = 3.32 (s, 3H), 3.55 (d, J = 12 Hz, 1H), 4.60 (d, J = 12 Hz, 1H), 7.13–7.23 (m, 2H), 7.34–7.41 (m, 1H), 7.60–7.65 (dd, J = 12 Hz, J = 3 Hz, 1H), 7.76–7.91 (m, 2H), 8.26–8.29 (dd, J = 9 Hz, J = 3 Hz, 1H) ppm. ¹³C NMR (75 MHz, [D6]DMSO): δ = 34.7, 38.3, 109.6, 110, 112.9, 113.2, 115.1, 119.3, 121, 128, 128.1, 128.9, 131.4, 139.2, 139.6, 139.7, 158.5, 158.6, 159.9, 163.2, 165.2, 166.9 ppm. HRMS (ESI−): calcd for C₁₆H₁₁BF₃N₂O₂ [M − H]⁻ 331.0866; found 331.0907.
4-(2-((Difluoroboranyl)oxy)phenyl)-8-fluoro-1-methyl-1,5-benzodiazepin-2-one 19b. (151 mg, 0.46 mmol, 91%), isolated as a yellow solid, mp = 238–240 °C. IR (ATR): ν_max: 916 (BN), 1065 (BF), 1183 (BF), 1677 (CN), 1592 (CO). ¹H NMR (300 MHz, [D6]DMSO): δ = 3.31 (s, 3H), 3.54 (d, J = 12 Hz, 1H), 4.60 (d, J = 12 Hz, 1H), 7.14–7.24 (m, 2H), 7.55–7.60 (m, 2H), 7.73–7.81 (m, 2H), 8.27–8.30 (dd, J = 9 Hz, J = 3 Hz, 1H) ppm. ¹³C NMR (75 MHz, [D6]DMSO): δ = 34.8, 38.3, 112, 112.4, 115, 117.3, 117.6, 119.4, 121.1, 125.1, 125.2, 131.6, 133, 133.2, 135, 139.6, 156.3, 158.7, 158.7, 159.5, 165.1, 167.9 ppm. HRMS (ESI−): calcd for C₁₆H₁₁BF₃N₂O₂ [M − H]⁻ 331.0866; found 331.0875.
4-(2-((Difluoroboranyl)oxy)phenyl)-7-nitro-1-methyl-1,5-benzodiazepin-2-one 20a. (147 mg, 0.41 mmol, 82%), isolated as a yellow solid, mp = 283–285 °C. IR (ATR): ν_max: 987 (BN), 1025 (BF), 1132 (BF), 1692 (CN), 1612 (CO). ¹H NMR (300 MHz, [D6]DMSO): δ = 3.40 (s, 3H), 3.60 (d, J = 12 Hz, 1H), 4.68 (d, J = 12 Hz, 1H), 7.16–7.26 (m, 2H), 7.82–7.87 (td, J = 9 Hz, J = 3 Hz, 1H), 8.07–8.10 (dd, J = 9 Hz, J = 3 Hz, 1H), 8.29–8.35 (m, 2H), 8.45 (d, J = 3 Hz, 1H) ppm. ¹³C NMR (75 MHz, [D6]DMSO): δ = 34.8, 38.4, 115.1, 118.7, 119.5, 119.9, 121.2, 127.7, 127.8, 131.8, 136.8, 138.8, 140.1, 159, 159.1, 165.2, 168.9 ppm. HRMS (ESI−): calcd for C₁₆H₁₁BF₂N₃O₄ [M − H]⁻ 358.0811; found 358.0805.
4-(2-((Difluoroboranyl)oxy)phenyl)-8-nitro-1-methyl-1,5-benzodiazepin-2-one 20b. (141 mg, 0.39 mmol, 79%), isolated as a yellow solid, mp = 295–297 °C. IR (ATR): ν_max: 929 (BN), 1049 (BF), 1145 (BF), 1708 (CN), 1618 (CO). ¹H NMR (300 MHz, [D6]DMSO): δ = 3.38 (s, 3H), 3.63 (d, J = 12 Hz, 1H), 4.71 (d, J = 12 Hz, 1H), 7.17–7.26 (m, 2H), 7.82–7.87 (td, J = 9 Hz, J = 3 Hz, 1H), 7.92 (d, J = 9 Hz, 1H), 8.32–8.35 (dd, J = 9 Hz, J = 3 Hz, 1H), 8.45–8.48 (dd, J = 9 Hz, J = 3 Hz, 1H), 8.66 (t, J = 3 Hz, 1H) ppm. ¹³C NMR (75 MHz, [D6]DMSO): δ = 35, 38.4, 115, 119.5, 121.2, 121.7, 121.8, 124.2, 124.5, 131.7, 132.1, 140, 143.2, 158.9, 158.9, 165.1, 166.7 ppm. HRMS (ESI−): calcd for C₁₆H₁₁BF₂N₃O₄ [M − H]⁻ 358.0811; found 358.0810.
4-(2-((Difluoroboranyl)oxy)-4-methoxyphenyl)-1-methyl-1,5-benzodiazepin-2-one 21. (159 mg, 0.46 mmol, 93%), isolated as a yellow solid, mp = 228–230 °C. IR (ATR): νmax: 950 (BN), 1033 (BF), 1148 (BF), 1610 (CO), 1685 (CN). ¹H NMR (300 MHz, [D6]DMSO): δ = 3.31 (s, 3H), 3.39 (d, J = 12 Hz, 1H), 3.91 (s, 3H), 4.46 (d, J = 12 Hz, 1H), 6.67–6.69 (m, 2H), 7.43–7.83 (m, 4H), 8.15 (d, J = 9 Hz, 1H) ppm. ¹³C NMR (75 MHz, [D6]DMSO): δ = 39.9, 43.3, 61.5, 107.3, 114.2, 115.6, 128, 130.7, 131, 134.6, 137.7, 138.4, 143.2, 166.7, 166.7, 170.6, 170.7, 173.7 ppm. HRMS (ESI+): calcd for C₁₇H₁₅BF₂N₂O₃ [M]⁺ 344.1143; found 344.1147.
4-(2-((Difluoroboranyl)oxy)-4-methoxyphenyl)-1-(prop-2-yn-1-yl)-1,5-benzodiazepin-2-one 22. (158 mg, 0.43 mmol, 86%), isolated as a yellow solid, mp = 160–162 °C. IR (ATR): ν_max: 1016 (BN), 1034 (BF), 1149 (BF), 1616 (CO), 1686 (CN). ¹H NMR (300 MHz, [D6]DMSO): δ = 3.26 (t, J = 3 Hz, 1H), 3.47 (d, J = 12 Hz, 1H), 3.91 (s, 3H), 4.50 (d, J = 12 Hz, 1H), 4.65 (d, J = 3 Hz, 2H), 6.67–6.81 (m, 2H), 7.45–7.84 (m, 4H), 8.17 (d, J = 9 Hz, 1H) ppm. ¹³C NMR (75 MHz, [D6]DMSO): δ = 36.3, 38, 56.3, 75.3, 78.9, 102.1, 108.9, 110.4, 122.7, 126, 126.1, 129.3, 133.1, 133.1, 136.2, 161.5, 164.7, 165.4, 168.5 ppm. HRMS (ESI−): calcd for C₁₉H₁₄BF₂N₂O₃ [M − H]⁻ 367.1066; found 367.1072.

4.2.5. Click chemistry.
1-((1-Benzyl-1H-1,2,3-triazol-4-yl)methyl)-4-(2-((difluoroboranyl)oxy)-4-methoxyphenyl)-1,5-benzodiazepin-2-one 23. to a mixture of compound 22 (184 mg, 0.5 mmol) and (azidomethyl)benzene (80 mg, 0.6 mmol, 1.2 eq.) in 5 mL DCM was added CuI (5 mg, 0.025 mmol, 5 mol%) and Et₃N (70 μL, 0.5 mmol, 1 eq.). The reaction mixture was stirred at room temperature for 3 h. The crude reaction was filtered through Celite®, the filtrate was concentrated under reduced pressure. The corresponding cycloadduct was obtained by crystallization in a minimum of Et₂O. The desired product (205 mg, 0.82 mmol, 82% yield) was obtained as a white solid, mp = 148–150 °C. IR (ATR): ν_max: 1016 (BN), 1052 (BF), 1143 (BF), 1617 (CO), 1687 (CN). ¹H NMR (300 MHz, [D6]DMSO): δ = 3.45 (d, J = 12 Hz, 1H), 3.91 (s, 3H), 4.48 (d, J = 12 Hz, 1H), 5.07 (s, 2H), 5.47 (d, J = 18 Hz, 1H), 5.53 (d, J = 18 Hz, 1H), 6.69–6.80 (m, 2H), 7.17–7.35 (m, 5H), 7.34 (m, 1H) 7.59 (m, 1H), 7.67 (s, 1H(triazole)), 7.81 (d, J = 6 Hz, 1H), 7.94 (d, J = 6 Hz, 1H), 8.15 (d, J = 9 Hz, 1H) ppm. ¹³C NMR (75 MHz, [D6]DMSO): δ = 42.9, 52.8, 56.3, 67, 102.1, 109, 110.4, 123.5, 126, 127.7, 128, 128.7, 129.3, 133.2, 135.8, 136.7, 142.8, 161.5, 161.6, 164.6, 165.6, 168.5 ppm. HRMS (ESI−): calcd for C₂₆H₂₁BF₂N₅O₃ [M − H]⁻ 500.1734; found 500.1712.

Acknowledgements

This work was also partially supported by Rouen University, INSA Rouen, Rouen University, the Centre National de la Recherche Scientifique (CNRS), Region Haute-Normandie (CRUNCh network), and the Labex SynOrg (ANR-11-LABX-0029). The authors are grateful to Mrs Amna Benzarti and Miss Nadia Msaddek, NMR service at the Faculty of Monastir, University of Monastir for the NMR analysis and to the Ministry of Higher Education and Scientific Research of Tunisia for financial support (LR11ES39). The authors also thank Albert Marcual (CNRS) for HRMS analyses, Patricia Martel (University of Rouen) for IR analyses, Dr Morgane Sanselme (University of Rouen) for X-ray diffraction analyses.

Notes and references

1. S. Atilgan, T. Ozdemir and E. U. Akkaya, Org. Lett., 2008, 10, 4065–4067.
2. L. Wu, A. Loudet, R. Barhoumi, R. C. Burghardt and K. Burgess, J. Am. Chem. Soc., 2009, 131, 9156–9157.
3. T. Rousseau, A. Cravino, E. Ripaud, P. Leriche, S. Rihn, A. De Nicola, R. Ziessel and J. Roncali, Chem. Commun., 2010, 46, 5082–5084.
4. H.-R. Zheng, L.-Y. Niu, Y.-Z. Chen, L.-Z. Wu, C.-H. Tunga and Q.-Z. Yang, RSC Adv., 2016, 6, 41002–41006.
5. For reviews on BODYPI dyes, see: (a) A. Loudet and K. Burgess, Chem. Rev., 2007, 107, 4891–4932; (b) R. Ziessel, G. Ulrich and A. Harriman, New J. Chem., 2007, 31, 496–501; (c) G. Ulrich, R. Ziessel and A. Harriman, Angew. Chem., Int. Ed, 2008, 47, 1184–1201.
6. C. Yu, Q. Wu, J. Wang, Y. Wei, E. Hao and L. Jiao, J. Org. Chem., 2016, 81, 3761–3770.
7. K. Benelhadj, J. Massue, P. Retailleau, S. Chibani, B. Le Guennic, D. Jacquemin, R. Ziessel and G. Ulrich, Eur. J. Org. Chem., 2014, 7156–7164 and references cited therein.
8. Y. Kubota, T. Tsuzuki, K. Funabiki, M. Ebihara and M. Matsui, Org. Lett., 2010, 12, 4010–4013.
9. S. M. Barbon, V. N. Staroverov and J. B. Gilroy, J. Org. Chem., 2015, 80, 5226–5235.
10. Y. Wu, H. Lu, S. Wang, Z. Li and Z. Shen, J. Mater. Chem. C, 2015, 3, 12281–12289.
11. (a) V. B. Kovalska, K. D. Volkova, A. V. Manaev, M. Y. Losytskyy, I. N. Okhrimenko, V. F. Traven and S. M. Yarmoluk, Dyes Pigm., 2010, 84, 159–164; (b) K. Kamada, T. Namikawa, S. Senatore, C. Matthews, P.-F. Lenne, O. Maury, C. Andraud, M. Ponce-Vargas, B. Le Guennic, D. Jacquemin, P. Agbo, D. D. An, S. S. Gauny, X. Liu, R. J. Abergel, F. Fages and A. D’Aléo, Chem.–Eur. J., 2016, 22, 5219–5232.
12. (a) H.-J. Son, W.-S. Han, K.-R. Wee, J.-Y. Chun, K.-B. Choi, S. J. Han, S.-N. Kwon, J. Ko, C. Lee and S. O. Kang, Eur. J. Inorg. Chem., 2009, 1503–1513; (b) A. Zakrzewska, E. Kolehmainen, A. Valkonen, E. Haapaniemi, K. Rissanen, L. Chęcińska and B. Ośmiałowski, J. Phys. Chem. A, 2013, 117, 252–256; (c) H. S. Kumbhar and G. S. Shankarling, Dyes Pigm., 2015, 122, 85–93; (d) K. Benelhadj, J. Massue and G. Ulrich, New J. Chem., 2016, 40, 5877–5884.
13. (a) D. Frath, S. Azizi, G. Ulrich, P. Retailleau and R. Ziessel, Org. Lett., 2011, 13, 3414–3417; (b) D. Frath, S. Azizi, G. Ulrich and R. Ziessel, Org. Lett., 2012, 14, 4774–4777; (c) S. Chibani, A. Charaf-Eddin, B. Le Guennic and D. Jacquemin, J. Chem. Theory Comput., 2013, 9, 3127–3135; (d) K. Dhanunjayarao, V. Mukundam, M. Ramesh and K. Venkatasubbaiah, Eur. J. Inorg. Chem., 2014, 539–545; (e) F. Cardona, J. Rocha, A. M. S. Silva and S. Guieu, Dyes Pigm., 2014, 111, 16–20; (f) J. Dobkowski, P. Wnuk, J. Buczyńska, M. Pszona, G. Orzanowska, D. Frath, G. Ulrich, J. Massue, S. Mosquera-Vázquez, E. Vauthey, C. Radzewicz, R. Ziessel and J. Waluk, Chem.–Eur. J., 2015, 21, 1312–1327; (g) G. Wesela-Bauman, M. Urban, S. Luliński, J. Serwatowski and K. Woźniak, Org. Biomol. Chem., 2015, 13, 3268–3279; (h) T. Tomakinian, R. Guillot, C. Kouklovsky and G. Vincent, Chem. Commun., 2016, 52, 5443–5446.
14. H. Mtiraoui, R. Gharbi, M. Msaddek, Y. Bretonnière, C. Andraud, C. Sabot and P.-Y. Renard, J. Org. Chem., 2016, 81, 4720–4727.
15. (a) Y. Kubota, H. Hara, S. Tanaka, K. Funabiki and M. Matsui, Org. Lett., 2011, 13, 6544–6547; (b) Y. Kubota, Y. Ozaki, K. Funabiki and M. Matsui, J. Org. Chem., 2013, 78, 7058–7067.
16. (a) H. C. Kolb, M. G. Finn and K. B. Sharpless, Angew. Chem., Int. Ed., 2001, 40, 2004–2021; (b) P. Thirumurugan, D. Matosiuk and K. Jozwiak, Chem. Rev., 2013, 113, 4905–4979.
17. Recent examples of ligation tools for the construction of (bio)molecular systems: (a) K. Hoogewijs, D. Buyst, J. M. Winne, J. C. Martins and A. Madder, Chem. Commun., 2013, 49, 2927–2929; (b) L.-A. Jouanno, A. Chevalier, N. Sekkat, N. Perzo, H. Castel, A. Romieu, N. Lange, C. Sabot and P.-Y. Renard, J. Org. Chem., 2014, 79, 10353–10366; (c) S. Hörner, C. Uth, O. Avrutina, H. Frauendorf, M. Wiessler and H. Kolmar, Chem. Commun., 2015, 51, 11130–11133; (d) A. Grassin, M. Claron and D. Boturyn, Chem.–Eur. J., 2015, 21, 6022–6026; (e) S. M. Agten, D. P. L. Suylen and T. M. Hackeng, Bioconjugate Chem., 2016, 27, 42–46; (f) B. Akgun and D. G. Hall, Angew. Chem., Int. Ed, 2016, 55, 3909–3913.
18. (a) M. Ipuy, Y.-Y. Liao, E. Jeanneau, P. L. Baldeck, Y. Bretonnière and C. Andraud, J. Mater. Chem. C, 2016, 4, 766–779; (b) J. C. de Mello, H. F. Wittmann and R. H. Friend, Adv. Mater., 1997, 9, 230; (c) L. Porrès, A. Holland, L.-O. PÅlsson, A. P. Monkman, C. Kemp and A. Beeby, J. Fluoresc., 2006, 16, 267.
19. A. M. Brouwer, Pure Appl. Chem., 2011, 83, 2213–2228.

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Footnote

† Electronic supplementary information (ESI) available. CCDC 1490358. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c6ra19246g

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