1,5-Benzodiazepin-2-ones: Investigation of a Family of Photoluminescent Materials

Article abstract of DOI:10.1021/acs.joc.6b00627

Photoluminescent materials, that are now ubiquitous in our everyday life, have particularly attracted the attention of the scientific community these past few years due to potential important applications such as in bioimaging, sensing, or optoelectronics

Full text of DOI:10.1021/acs.joc.6b00627

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Article
1,5-Benzodiazepin-2-ones : Investigation
of a Family of Photoluminescent Materials
Hasan Mtiraoui, Rafik Gharbi, Moncef Msaddek, Yann Bretonnière,
Chantal Andraud, Cyrille Sabot, and Pierre-Yves Renard
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b00627 • Publication Date (Web): 29 Apr 2016
Downloaded from http://pubs.acs.org on May 2, 2016
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1,5ꢀBenzodiazepinꢀ2ꢀones : Investigation of a Family
of Photoluminescent Materials
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Hasan Mtiraoui,a Rafik Gharbi;a Moncef Msaddek,a,* Yann Bretonnière,b Chantal Andraud,b Cyrille
Sabot,c,* Pierre-Yves Renard c
a Université Monastir, Laboratory of Heterocyclic Chemistry Natural Products and Reactivity/CHPNR,
Department of Chemistry, Faculty of Science of Monastir, 5000 Monastir (Tunisia)
b Université Lyon, ENS de Lyon, CNRS, Université Lyon 1, Laboratoire de Chimie, 69342 Lyon,
(France).
c Normandie Univ, COBRA, UMR 6014 & FR 3038; Univ Rouen; INSA Rouen; CNRS, 1 rue Tesnière
76821 MontꢀSaintꢀAignan, Cedex (France)
Fax: + 33 (0)2 35 52 29 71; Tel: + 33 (0)2 35 52 24 39
Eꢀmail: moncef.Msaddek@fsm.rnu.tn and cyrille.sabot@univꢀrouen.fr
Table of Contents Graphic:
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Abstract: Photoluminescent materials, that are now ubiquitous in our everyday life, have particularly
attracted the attention of the scientific community these last few years due to potential important
applications such as in bioꢀimaging, sensing or optoelectronics. In this context, relatively few different
families of molecules have been reported to exhibit fluorescence in the aggregated or solidꢀstate through
the excitedꢀstate intramolecular proton transfer (ESIPT) photochemical process. Here is reported the
preparation and subsequent determination of photochemical properties of an underexplored family of
1,5ꢀbenzodiazepinꢀ2ꢀone derivatives. From these data and Xꢀray diffraction analysis study, it emerged
that photoluminescence (in the range 520ꢀ655 nm) was mostly attributed to ESIPT. The
photoluminescent potential of 1,5ꢀbenzodiazepinꢀ2ꢀones, their facile access and functionalization was
demonstrated through the preparation of two fluorogenic probes for the selective detection of biothiols.
Introduction:
While conventional organic fluorescent dyes exhibit strong fluorescence specifically in diluted
solution, a growing number of photoluminescent materials reported in the literature are, on the other
hand, emissive only in their aggregated or solidꢀstate.1 This singular photophysical phenomenon has
been leveraged in highꢀtech applications of general interest including organic lightꢀemitting diodes
(OLEDs), organic photovoltaics (OPV), organic solidꢀstate lasers, and in the design of chemoꢀ and
biosensors with useful applications in environmental and biomedical sciences.2 Furthermore, the
aggregationꢀinduced emission (AIE) process provides a useful complementary strategy to the use of
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conventional hydrophobic organic fluorescent dyes, which tend to form nonꢀemissive aggregates in
physiological conditions, a phenomenon also referred to as aggregationꢀcaused quenching (ACQ).3
A lot of efforts have been devoted to rationalize the unusual luminescent behavior arising from the
restriction of intramolecular motions of dye aggregates or solidꢀstate luminescent materials, and
different explanations have been suggested according to the dye structure, including: intramolecular
charge transfer (ICT), restricted intramolecular rotations (RIR), restricted intramolecular vibrations
(RIV), twisted intramolecular chargeꢀtransfer (TICT), excitedꢀstate intramolecular proton transfer
(ESIPT). In the ESIPT photochemical process, the dye conformation in the aggregated or solidꢀstate is
locked by the formation of an intramolecular Hꢀbonding between a proton donor (i.e. an hydroxyl or
amino group) and a proton acceptor (i.e. a cabonyl or an imino group), and undergoes a radiative enol
(E) ꢀ keto (K) tautomerization through a fourꢀstep EꢀE*ꢀK*ꢀK process, upon photoexcitation (Scheme
1).4
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Scheme 1. ESIPT principle
The significant structural difference between the excited species (E) and the emissive species
(K*) gives rise to large Stokes’ shifts, which advantageously decreases the spectral overlap between the
dye’s absorption and emission peaks.5 Different dyes emitting in the aggregate or solidꢀstate using
ESIPT have been reported, among others, hydroxyphenyl benzothiazole, hydroxyphenyl
imidazopyridine or hydroxyphenyl benzazoles dyes.6 Besides, in the course of studies on the biological
properties and synthetic applications of 4ꢀ(2ꢀhydroxyphenyl)ꢀ1,3ꢀdihydroꢀ1,5ꢀbenzodiazepinꢀ2ꢀones, it
has been observed that this class of compounds shows bright fluorescence in the visible region in
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particular in the solid state. Surprisingly, to the best of our knowledge, photophysical properties of such
derivatives have never been thoroughly investigated yet.7
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Reported herein are the photophysical properties of a novel class of luminescent materials based
on the 2ꢀhydroxyphenylꢀ1,5ꢀbenzodiazepinꢀ2ꢀone scaffold. Substituent effects on the fluorescence
properties have been investigated in order to determine factors that govern the fluorescence emission,
and more generally to understand the mechanism of photoluminescence. Finally, the 1,5ꢀbenzodiazepinꢀ
2ꢀone platform has been used to design two fluorogenic probes for the selective detection of biothiols.
Results and Discussion:
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A series of 4ꢀphenylꢀ1,3ꢀdihydroꢀ1,5ꢀbenzodiazepinꢀ2ꢀones variously substituted either on the
aromatic rings or on the amide moiety were prepared. First, modifications on the fused aromatic ring
system were achieved according to known procedures, i.e. by reacting 4ꢀhydroxycoumarin with
unsubstituted or 4ꢀsubstituted 1,2ꢀphenylenediamines in refluxing pꢀxylene for 3 h (Table 1).8,9 Whereas
these transformations worked well, we observed however, the formation of two regioisomers in each
case, the predominant product being substituted at position 8 of the benzodiazepinꢀ2ꢀone for Me, Br, Cl,
F, and at position 7 for NO2. For compounds 3ꢀ6, the mixture of regioisomers was readily separated by
column chromatography on silica gel (Experimental Section), however, the reaction carried out with 4ꢀ
methylꢀoꢀphenylenediamine gave an inseparable mixture of benzodiazepinꢀ2ꢀone regioisomers 2a/b in a
75% yield and an isomeric ratio of 1.56:1, which was used as such.
Table 1. Modifications on the fused aromatic ring system
entry
R
cmpd
yield (%)a
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H
Me
Br
85a
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8
75b
2a/b
3a/b
4a/b
5a/b
6a/b
58/15 (73)c
72/18 (90)c
65/18 (83)c
8/35 (43)c
Cl
F
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NO2
a Isolated yield. b Isolated as an inseparable mixture of regioisomers. c Combined yield.
Next, benzodiazepinꢀ2ꢀones 7 and 8 with modifications on the phenyl ring have been prepared in 90%
10,11
and 84% yield respectively, from benzoylacetates (Scheme 2).
Finally, the Nꢀmethylation of the
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amide function of the derivative 1 afforded the analogue 9 in good 90% yield.
Scheme 2. Modifications on the phenyl ring system or amide function
With these compounds in hand, their photophysical properties were determined, and summarized in
Table 2.
Table 2. Photophysical data for compounds 1ꢀ9
stokes shift
λabs
(nm)
λem
(nm)
entry
1
cmpd
solution/solid
Φ
F
(nm)
a
a
a
b
b
CH3CN
EtOH
PBS
346
346
352
1
a
529
177
0.05c
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d
d
Solid
PBS
Solid
PBS
Solid
PBS
Solid
PBS
Solid
PBS
Solid
PBS
Solid
PBS
Solid
PBS
Solid
PBS
Solid
PBS
Solid
PBS
Solid
PBS
Solid
543
0.26e
0.16c
0.30e
0.06c
0.34e
0.05c
~0.02e
0.08c
0.14e
0.06c
0.10e
0.09c
0.18e
0.04c
1
2
3
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7
8
9
2
3
360
522
538
531
546
523
535
523
520
531
533
523
527
536
162
2a/b
3a
3b
4a
4b
5a
5b
6a
6b
7
d
d
360
171
d
d
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350
163
d
d
5
360
163
d
d
6
370
161
d
d
7
360
163
d
d
8
347
189
d
d
562
0.14e
a
a
d
a
d
a
a
a
a
a
d
b
9
358
d
570
<0.01e
a
b
10
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13
370
d
655
~0.01e
a
b
310
a
a
a
a
a
b
b
b
b
8
307
a
9
335
d
540
0.35e
a
b
c
Not applicable. Not fluorescent. Measurement determined at 25 °C by a relative method using
quinine sulfate as standard (ΦF = 0.52 in 0.05 M H2SO4) with excitation at 350 nm.20 Not determined.
d
e
Measurement determined at 25 °C by integrating sphere.
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First, our study was focused on the unfunctionalized 4ꢀ(2ꢀhydroxyphenyl)ꢀ1,3ꢀdihydroꢀ1,5ꢀ
1
2
benzodiazepinꢀ2ꢀone 1 in order to unambiguously determine the mechanism of photoluminescence of
this family of molecules. In solution, the benzodiazepinꢀ2ꢀone displayed a fluorescence emission (ΦF =
0.05, entry 1) only in aqueous media such as 0.1 M PBS pH 7.4, in which 1 gave a slightly cloudy
solution. The benzodiazepinꢀ2ꢀone was more emissive in the solid state, exhibiting an encouraging
quantum yield of 0.26 and a large stokes shift (~175 nm), which is in the range of those generally
observed with ESIPT molecules. The absorption and emission spectra of 1 were measured, as depicted
in Figure 2, in various solvents ranging from apolar aprotic to polar protic in order to investigate the
AIE hypothesis. In solvents in which 1 was well dispersed, such as EtOAc, THF, DCM, MeCN or
EtOH, no significant modifications of the absorbance profile of 1 were noticed, the positions and
intensities of absorption bands being almost the same. In contrast, in water and PBS, a flattening of the
absorption bands was observed, probably due to the fact that 1 forms aggregates in these solvents.
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Figure 1. Absorption (a) and emission (b) spectra of 1 (c = 3.96 10ꢀ5 mol/L) in various solvents at
25 °C upon an excitation at 330 nm.
The fluorescence emission spectra of the benzodiazepinꢀ2ꢀone 1 were determined at 330 nm
excitation (Figure 1b). The spectra obtained in all organic solvents showed no fluorescence emission,
fluorescence was observed only in aqueous media, which is consistent with the AIE hypothesis. Next,
the absorption and emission spectra of 1 were recorded in THF/water mixtures with various water
fractions (from 1:99 to 99:1, v/v) in order to further confirm the AIE effect (Figures 2a and b). As the
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water fraction increased, the intensity of the absorption bands around 340 nm decreased, in particular
for a THF/water solution having a ratio of 1:99, probably due to the formation of insoluble aggregates.
Besides, no photoluminescence was observed upon an excitation at 330 nm in mixtures rich in THF, for
which 1 is well dispersed. On the other hand, in THF/water mixtures with high water contents (i.e. >
70%), the benzodiazepinꢀ2ꢀone 1 became markedly more emissive (Figure 2c), which is still in line with
the AIE mechanism. The conformational rigidity of 1 imposed in the solidꢀstate favors the formation of
a radiative 6ꢀmembered ring Hꢀbonding system responsible for the ESIPT effect. In contrast, in the
solution state, intramolecular motions (such as rotations of the phenol ring of 1 around the CꢀC bond)
are not restricted anymore in the excitedꢀstate, favoring thus a nonꢀradiative deexcitation process.
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Figure 2. Absorption (a) and emission (b) spectra of 1 at 25 °C at various THF/water ratios. (c)
Effect of water fraction on the fluorescence intensity of 1 determined at 529 nm upon an excitation
at 330 nm at 25 °C.
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Crystals for Xꢀray analysis were obtained by slow evaporation of a DMF solution of 1. The crystal
1
2
structure of 1 has been determined from single crystal Xꢀray diffraction. Interestingly, it appears that
compound 1 establishes strong intraꢀ and intermolecular OꢀH...N hydrogen bonds in the crystalline state
at a distance of 1.82 and 2.10 Å, respectively (Figure 3a). The corresponding dimers are stacked, their
cohesion being ensured by πꢀπ interactions along aꢀaxis, and van der Waals interactions along bꢀ, and cꢀ
axes (Figure 3b). The small torsion angle (3.7 °) between the phenol and imineꢀring system (i.e. C7ꢀC8ꢀ
C9ꢀO1) is in accordance with the ESIPT phenomenon. On the other hand, an important torsion angle
(74.0 °) is observed within the 7ꢀmembered ring system (N1ꢀC7ꢀC14ꢀC15) presumably due to the sp3
geometry of the C3 carbon atom. This results in a deviation of the backbone of the molecule from the
planar structure, giving rise to a herringbone arrangement through the establishment of intermolecular
hydrogen bonding interactions.
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Figure 3. Crystal structure of compound 1: a) thermal ellipsoidal representation (50% of
probability); b) representation of dimers, the cohesion being ensured by hydrogen bond (dashed
pink lines) and πꢀπ interactions (dashed yellow lines); c) projection along a axis, the cohesion
being ensured by van der Waals interactions.
Next, the effect of structural modifications of 1 located either on the phenyl moiety, the fused
ring system, or the NꢀH amide function on the photoluminescence properties were studied by recording
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the absorption and emission spectra of a range of analogues 2ꢀ9 (Table 2). It should be stressed that, as
compound 1, all these compounds were nonꢀemissive in acetonitrile or ethanol, i.e. in solution state. As
expected, the hydroxyl group on the phenyl ring proved crucial since the analogue 7 did not show any
fluorescence emission neither in PBS nor in the solidꢀstate upon an excitation at 350 nm (entry 11).
Similarly, the replacement of the acidic hydrogen atom of the hydroxyl moiety by a methyl group in
compound 8 suppressed completely the photoluminescence both in solution and solid phase
environments (entry 12). This result suggests that luminescence is solely produced by the ESIPT
mechanism, an electronic pushꢀpull (methoxyꢀimine) process being by itself insufficient. Besides, the
introduction of an electron donating and lipophilic methyl group on the phenyl moiety of the fused ring
system has a beneficial effect on quantum yields, particularly in PBS (0.16, entry 2), which may be
ascribed to an increase in hydrophobicity that favors aggregation. On the other hand, halogen atoms
cause a substantial decrease in the fluorescence intensity except for the 8ꢀbromo substituted compound
3a whose quantum yields are similar to that of compound 1 (0.06 in PBS and 34% in the solidꢀstate,
entry 3). Substitution at the position 7 of the fused ring system by a fluorine atom causes a 19 nm
bathochromic shift in the emission wavelength maxima in the solid state (entry 8). In addition, the
strong electron withdrawing nitro group leads to almost the vanishing of the photoluminescence, but a
remarkable (112 nm) bathochromic shift of the emission spectra in the farꢀred region (655 nm, entry
10). NꢀMethylation of the amide function of the 7ꢀmembered ring system increases the fluorescence in
the solid state (0.35, entry 13), and interestingly, turns off the photoluminescence in PBS. Although this
latter result may seem intriguing in view of the moderate quantum yield observed in PBS for its
isomeric analogues 2a/b, it is nevertheless consistent with the significant role played by intermolecular
hydrogen bonding interactions in the crystalline state (c.f. Figure 3) and consequently in the AIE
behavior. 12 Indeed, as can be seen from the Xꢀray diffraction of compound 9 (Figure 4), the presence of
a methyl group on the nitrogen atom eliminates the intermolecular hydrogen bonding interactions
observed for compound 1, the internal hydrogen bond being however preserved, ensuring the
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occurrence of ESIPT. Consequently, collectively these data highlights the importance of strong
intermolecular hydrogen bonding interactions to enable AIE behavior.
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Figure 4. Crystal structure of compound 9: a) thermal ellipsoidal representation (50% of
probability); b) a packing view along b axis.
To examine the potential of benzodiazepinꢀ2ꢀone derivatives as effective precursors of profluorescent
probes, the design of solidꢀstate ESIPT fluorescent probes for the selective detection of biothiols
directly from TLC plates was next investigated.13 Due to the biological significance of thiols, the
development of small organic fluorogenic probes for their rapid and specific detection in various
aqueous matrices has become an intensive field of research in the few last years. To this end, several
thiolꢀspecific reactions have been used to design these probes including among others, reduction
reactions, aromatic nucleophilic substitutions, Michael additions, disulfide exchanges. 14 In this context,
the 2,4ꢀdinitrobenzene sulfonyl (DNBS) group proved to efficiently quench the fluorescence through a
photoinduced electron transfer (PeT) process when attached to a fluorescent molecule.15
Advantageously, this group is then easily removed in the presence of biothiols through an SNAr process,
restoring thus the fluorescence of the parent compound (Scheme 3).
NO2
O2N
O
NO2
R2S
R2SH
OH
S
R1
R1
+ SO2
+
O
O
NO2
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Scheme 3. Principle of the DNBSꢀbased fluorogenic probes for biothiols detection
1
2
3
4
5
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7
8
9
Then, the design of a solidꢀstate fluorescent probe for the detection of total biothiols directly from
TLC plates was first investigated by conjugating the green emissive compound 1 with 2,4ꢀ
dinitrobenzenesulfonyl (DNBS) group (Scheme 4). The desired probe 10 was obtained in 85% yield.
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1
The regioselective Oꢀsulfonylation of the transformation was confirmed by both H NMR analysis that
showed the complete disappearance of the proton peak at 14 ppm corresponding to the phenol group of
1, and 1Hꢀ13C HMBC NMR experiment that unambiguously exhibited a correlation between the NꢀH
proton and the C3 carbon atom (c.f. supporting information).
Scheme 4. Preparation of probes 10 and 11 for fluorescence sensor applications
With the probe in hand, its ability to selectivity detect thiolꢀcontaining amino acids over other
biologically relevant species directly on TLC plates was investigated by dropping a ~10 mM solution of
each corresponding amino acid (2 × 9 ꢁL) in PBS 7.4 on the probe spots (5 ꢁL of a ~2 mM solution in
THF). The eluted TLC (EtOAC/cyclohexane 1:1) was next visualized under visible and UV light (365
nm), and as one might expect, the fluorescence emission was observed in the presence of free thiolꢀ
containing biological species (i.e. cysteine, glutathione GSH, and bovine serum albumin BSA) only. In
sharp contrast, no fluorescent spots were detected for all other Oꢀ and Nꢀnucleophilic species tested,
showing the compatibility of the DNBS approach with the 1,5ꢀbenzodiazepinꢀ2ꢀone scaffold (Figure 5a
and b).
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Figure 5. Photographs of TLC plates taken under visible light (a) or under 365 nm UV
illumination (b) showing the detection of total biothiols in the presence of the probe 10.
Photographs of TLC plates taken under visible light (c) or under 365 nm UV illumination (d)
showing the detection of cysteine in the presence of the probe 11.
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Following these encouraging results, the masking of the fluorophore with acrylate was also
envisioned in order to specifically detect cysteine over other biological species (including peptide thiols
such as GSH).16 Indeed, while a thiol ether linkage is formed upon the conjugate addition of thiols to
acrylates, the fluorescent molecule is released only upon the second step of intramolecular ester
aminolysis. Accordingly, the acrylateꢀbased probe 11 synthetized in 75% yield from 1 was subjected to
a similar TLC experiment to that performed previously with the probe 10 (Figures 5c and d). The
fluorescence emission was observed only in the presence of cysteine, GSH and BSA producing no
luminescent response, which is in accordance with the mechanism of action of such reported acrylateꢀ
based fluorogenic probes designed for the detection of cysteine. The approximate detection limit for
probe 10 and 11 towards cysteine was determined to be in the range of 2ꢀ20 ꢁM (c.f. Supporting
Information). Interestingly, the combination of TLC results obtained with probes 10 and 11 would also
provide valuable information regarding the presence (or not) of peptide thiols in the biological medium
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investigated. This was illustrated with BSA whose TLC results suggested the presence of peptide thiols,
but not of free cysteine (dashed white rectangle, Figures 5b and d).17
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Conclusion:
9
We have reported the preparation of a family of 1,5ꢀbenzodiazepinꢀ2ꢀone analogues, whose
promising photophysical properties were hitherto underexplored. Fluorescence spectroscopic results and
Xꢀray diffraction analyses showed that their photoluminescence was mostly ensured by ESIPT in the
aggregated and solidꢀstate, favored by strong intermolecular interactions. Interestingly, it appeared that
the dimeric intermolecular NH...O hydrogen bonding was not essential for the fluorescence in the solidꢀ
state.
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EXPERIMENTAL SECTION
All solvents were dried following standard procedures: toluene, methylene chloride (DCM) were
obtained from a solvent drying system. THF: distillation over Na°/benzophenone. Commercially
available reagents were used without further purification, unless otherwise stated. All reactions
involving airꢀ and moisture sensitive reagents were performed under Argon using syringeꢀseptum cap
technique. Column chromatography purifications were performed on silica gel (40ꢀ63 ꢁm). Thinꢀlayer
chromatography (TLC) analyses were carried out on Fꢀ254 aluminum sheets. The spots were visualized
through illumination with UV lamp (λ = 254 nm) and/or staining with KMnO4. Phosphate buffered
saline PBS (0.1 M, pH 7.4) was prepared using water purified with a MilliꢀQ system (purified to 18.2
Mꢂ.cm).
Instruments and methods
1
IR spectra were recorded with a universal ATR sampling accessory. H 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 nonꢀdeuterated solvent signal: DMSOꢀd6 (δΗ =
2.50, δC = 39.52).18 Multiplicities are described as s (singlet), d (doublet), dd, ddd, etc. (doublet of
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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. Highꢀresolution mass
spectra (HRMS) were obtained using an orthogonal acceleration timeꢀofꢀflight (oaꢀTOF) mass
spectrometer equipped with an electrospray source and in the positive and negative modes (ESI+/ꢀ).
Lowꢀresolution mass spectra (LRMS) were obtained with a mass spectrometer equipped with an ESI
source. UVꢀvisible spectra were obtained using a rectangular quartz cell (Open Top, 10 × 10 mm, 3.5
mL). Regarding the solvent effect on the absorption and emission spectra of compound 1 (Figure 1), 30
ꢁL of a stock solution (1 mg/mL) of 1 in DMSO was diluted in 2970 ꢁL of the corresponding solvent,
except for the cyclohexane that required for miscibility reasons the preparation of a stock solution (1
mg/mL) of 1 in THF. Solidꢀstate fluorescence quantum yields were determined using an integrating
sphere instrument according to a reported method.19 Fluorescence spectroscopic studies in solution were
performed with a semiꢀmicro quartz fluorescence cell (light patch base thickness 10 × 4 mm, chamber
volume: 1400 ꢁL), 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 quinine sulfate (ΦF = 52 % in 0.05 M H2SO4)20 as a standard. The following
equation was used to determine the relative fluorescence quantum yield in solution:
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ΦF(x) = (AS/AX)(FX/FS)(nX/nS)2ΦF(s)
where A is the absorbance (in the range of 0.01ꢀ0.1 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 water, 1.337 for PBS.
General Procedure for the synthesis of compounds 1, 2a/bꢀ6a/b, 7.
A solution of 4ꢀhydroxycoumarin (1.62 g, 10 mmol) and the appropriate 1,2ꢀphenylenediamine
derivative (10 mmol, 1 equiv.) in pꢀxylene (50 ml) or acetic acid/ethanol (40 mL, 1:1, v/v) was refluxed
for 3 h. Then, the reaction mixture was cooled to RT, filtered, and the precipitate washed with methanol
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several times. Silica gel column chromatography of the precipitate was performed to separate the two
regioisomers.
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Compounds 18 and 711 were prepared according to an experimental procedure reported in the literature.
Mixture of 4-(2-hydroxyphenyl)-8-methyl-1,5-benzodiazepin-2-one and 4-(2-hydroxyphenyl)-7-methyl-1,5-
benzodiazepin-2-one 2a/b: It was isolated by chromatography on silica gel as a yellow solid and as an
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inseparable mixture of regioisomers of 2a and 2b in a 1.56:1 ratio (2 g, 75% yield) 8,9
3150 (NH), 3100 (OH) 1670 (CN), 1585 (CO). 1H NMR (300 MHz, DMSOꢀd6): δ =
.
mp = 299ꢀ301
°C. IR (ATR): νmax
:
2.35 (s, 5 H), 3.59 (s, 3.2 H), 7.11ꢀ7.31(m, 6.6H), 7.42ꢀ7.64 (m, 3.3 H), 8.5ꢀ8.08 (m, 1.6H), 10.6 (s, 1H),
13
10.67 (s, 0.64H), 14.15 (s, 1H), 14.16 (s, 0.6H) ppm. C NMR (75 MHz, DMSOꢀd6): δ =20.2, 20.6,
38.5, 117.6, 117.6, 118.1, 118.2, 118.9, 122, 125.5, 127.1, 127.3, 128.1, 128.8, 129.6, 129.6, 131, 133.7,
133.9, 133.9, 134, 136, 136.9, 161.4, 161.5, 162.3, 1162.8, 165.8 ppm.
8-Bromo-4-(2-hydroxyphenyl)-1,5-benzodiazepin-2-one 3a and 7-bromo-4-(2-hydroxyphenyl)-1,5-
benzodiazepin-2-one 3b. The two regioisomers (3a/b) were separated by chromatography on silica gel
(EtOAc/cyclohexane, 1:1, v/v) to give the compound 3a (1.91 g, 58% yield), which has already been
characterized,9 and 3b (0.495 g, 15% yield), both as yellow solids (3b eluted first). Compound 3b: mp =
279ꢀ281 °C. IR (ATR): νmax:
3333 (NH), 3205 (OH) 1673 (CN), 1600 (CO). 1H NMR (300 MHz, DMSOꢀ
d6): δ = 3.66 (s, 2H), 6.97ꢀ7.02 (m, 2H), 7.42ꢀ7.5 (m, 4H), 7.92 (d, J = 7.2 Hz, 1H), 10.80 (s, 1H), 13.77
(s, 1H) ppm. 13C NMR (75 MHz, DMSOꢀd6): δ =38.8, 117.6, 118.2, 119, 119, 124.2, 127.2, 129.4,
129.8, 132.5, 134.1, 135.6, 161.3, 163.5, 165.9, ppm. HRMS (ESI+): calcd. for C15H12BrN2O2 [M+H]+
331.0082; found 331.0088.
8-Chloro-4-(2-hydroxyphenyl) -1,5-benzodiazepin-2-one 4a and 7-chloro-4-(2-hydroxyphenyl) -1,5-
benzodiazepin-2-one 4b. The two regioisomers (4a/b) were separated by chromatography on silica gel
(EtOAc/cyclohexane, 1:1, v/v) to give the compound 4a (2.05 g, 72% yield), which has already been
characterized 8 and 4b (0.51 g, 18% yield), both as yellow solids (4b eluted first). Compound 4b: mp =
269ꢀ271 °C. IR (ATR): νmax:
3105 (NH), 2916 (OH), 1682(CN), 1611(CO). 1H NMR (300 MHz, DMSOꢀ
d6): δ = 3.67 (s, 2H), 6.97ꢀ7.02 (m, 2H), 7.28ꢀ7.33 (m, 2H), 7.44ꢀ7.52 (m, 2H), 7.91 (d, J = 7.8 Hz,1 H ),
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10.81 (s, 1H), 13.78 (s, 1H) ppm. C NMR (75 MHz, DMSOꢀd6): δ =38.7, 117.7, 118.2, 119, 121.3,
124.4, 129.2, 130.8, 132.3, 134.1, 135.3, 161.3, 163.4, 165.9 ppm. HRMS (ESI+): calcd. for
C15H12ClN2O2 [M+H]+· 287.0587; found 287.0593.
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8-Fluoro-4-(2-hydroxyphenyl) -1,5-benzodiazepin-2-one 5a and 7-fluoro-4-(2-hydroxyphenyl) -1,5-
benzodiazepin-2-one 5b: The two regioisomers (5a/b) were separated by chromatography on silica gel
(EtOAc/cyclohexane 1:1, v/v) to give the compound 5a (1.75 g, 65% yield) and 5b (0.54 g, 18% yield),
which has already been characterized,8 both as yellow solids (5b eluted first). Compound 5b: mp = 289ꢀ
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281 °C. IR (ATR): νmax:
3160 (NH), 3100 (OH) 1686 (CN), 1591 (CO).1H NMR (300 MHz, DMSOꢀd6): δ =
3.66 (s, 2H), 6.97ꢀ7.06 (m, 3H), 7.12ꢀ7.19 (td, J = 8.1 Hz, 2.7 Hz, 1 H), 7.43ꢀ7.56(m, 2H), 7.91 (dd, J =
8.7 Hz, 1.5 Hz, 1 H ), 10.85 (s, 1H), 13.90 (s, 1H) ppm. 13C NMR (75 MHz, DMSOꢀd6): δ =38.6, 107.8,
108.2, 111.8, 112.1, 117.6, 118.2, 119, 129.5, 139.6, 129.7, 132.4, 132.5, 133.2, 133.2, 133.9, 158.4,
19F NMR (282 MHz, DMSOꢀd ): δ= ꢀ114.70 ppm
161.3, 161.7, 162.7, 165.8 ppm.
. HRMS (ESI+):
6
calcd. for C15H12 FN2O2 [M+H]+ 271.0873; found 271.0883.
4-(2-Hydroxyphenyl)-8-nitro-1,5-benzodiazepin-2-one
6a
and
4-(2-hydroxyphenyl)-7-nitro-1,5-
benzodiazepin-2-one 6b. The two regioisomers (6a/b) were separated by chromatography on silica gel
(EtOAc/cyclohexane, 1:1, v/v) to give the title compounds 6b (1.03g, 35% yield), which has already
been characterized,9 and 6a (0,230 g, 8% yield) as yellow solids (6b eluted first). Compound 6a: mp =
301ꢀ303 °C. IR (ATR): νmax: 3105 (NH), 2969(OH), 1675(CN), 1620(CO). 1H NMR (300 MHz, DMSOꢀd6):
δ = 3.76 (s, 2 H), 7.03 (m, 2H), 7.41ꢀ7.53 (m, 2H), 7.94ꢀ7.96 (m, 1H), 8.17ꢀ8.20 (m, 1H), 8.34(s, 1H),
11.25 (s, 1H), 13.32 (s, 1H) ppm. 13C NMR (75 MHz, DMSOꢀd6): δ = 39.3, 117.7, 118.2, 119.2, 121.5,
122.9, 123.3, 130.1, 134.5, 136.2, 136.8, 143.1, 161.1, 16.9, 165.9 ppm. HRMS (ESI+): calcd. for
C15H12N3O4 [M+H]+·298.0826; found 298.0824.
4-(2-Methoxyphenyl)-1,5-benzodiazepin-2-one 8. To a stirred boiling solution of benzeneꢀ1,2ꢀdiamine
(1.08 g, 0.1 mol) in pꢀxylene (10 mL), methyl 3ꢀ(2ꢀmethoxyphenyl)ꢀ3ꢀoxopropanoate21 was added (2.49
g, 0.12 mol) dropwise and refluxed for 2 h. The reaction mixture was left to stand at room temperature
for 24 h. The precipitated solid was collected by filtration and recrystallized from ethanol to give the
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desired product (2.23 g, 84 % yield) as white solid. mp = 198ꢀ200 °C. IR (ATR): νmax: 3190(NH), 1680
(CN), 1611 (CO). 1H NMR (300 MHz, DMSOꢀd6): δ = 3.39 (s, 2H), 3.39 (s, 3H), 6.99 (td, J = 7.5 Hz,
0.9 Hz, 1 H), 7.18(m, 4H), 7.33 (m, 1H), 7.43 (m, 1H ), 10.38 (s, 1H) ppm. 13C NMR (75 MHz, DMSOꢀ
d6): δ = 43.3, 55.5, 111.9, 120.3, 121.4, 123.8, 126.1, 127.9, 128.7, 129.9, 130.2, 131.7, 139.0, 157.6,
160.9, 167.2 ppm. HRMS (ESI+): calcd. for C16H15N2O2 [M+H]+·267.1134; found 267.1126.
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4-(2-Hydroxyphenyl)-1-methyl-1,5-benzodiazepin-2-one 9. To a solution of 4ꢀ(2'ꢀhydroxypheny1)ꢀ1,5ꢀ
benzodiazepinꢀ2ꢀone 1 (1.01 g, 4 mmol) in anhydrous THF (50 mL) at 0 ° C, was added NaH (60% in
mineral oil, (0.176 g, 4.4 mmol, 1.1 equiv.). The mixture was stirred for 10 to 15 min before the
addition of methyl iodide (0.498 mL, 8 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) and
the desired product was obtained (0.95 g, 90% yield) as yellow solid. mp = 172ꢀ174 °C. IR (ATR): νmax
:
3100 (OH), 1661 (CN), 1593 (CO).1H NMR (300 MHz, CDCl3): δ =
3.05 (d, J= 12 Hz, 1H), 3.32(s, 3H),
4.3(d, J=12 Hz, 1H), 6.96ꢀ7.02(m, 2H), 7.33ꢀ7.49 (m, 4H), 7.56ꢀ7.59 (
dd, J = 8.4 Hz, 1.5 Hz, 1H),7.92ꢀ
(
7.95 dd, J = 8.1 Hz, 1.5 Hz, 1H),
13C NMR (75 MHz, DMSOꢀd6): δ=34.8, 37.9,
13.94 (s, 1H) ppm,
117.6, 117.8, 118.6, 119, 122.5, 125.3, 126.6, 127.2, 129.9, 134, 135.7, 137.7, 161.3, 164.8, 165.3.
HRMS (ESI+): calcd. for C16H15N2O2 [M+H]+·267.1134; found 267.1125.
4-(Phenyl (2-(2,4-dinitrobenzenesulfonate))-1,5-benzodiazepin-2-one 10: To
a
solution of 4ꢀ(2'ꢀ
hydroxypheny1)ꢀ1,5ꢀbenzodiazepinꢀ2ꢀone 1 (0.25g, 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 reaction mixture was stirred for 10
to 15 min before the addition of 2,4ꢀdinitrobenzenesulfonyl chloride (0.292 g, 1.1 mmol, 1.1 equiv.).
The reaction mixture was maintained at 0 °C for 30 min, and THF is then removed under pressure, and
purified by flash column chromatography on silica gel (Cyclohexane/EtOAc from 100:0 to 80:20) to
obtained the titled compound (0.41 g, 85% yield) as white solid. mp = 199ꢀ201 °C IR (ATR): νmax
:
1
2.92 (d, J= 12 Hz, 1H), 3.36(s, 2H),
2975(NH), 1672(CN), 1613(CO). H NMR (300 MHz, CDCl3): δ =
7.11ꢀ7.31(m, 5H), 7.58ꢀ7.76 (m, 3H), 8.22 (
(
d, J = 9 Hz, 1H), 8.48ꢀ8.52 dd, J = 9 Hz, 3 Hz, 1H), 8.93(d,
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, 10.54 (s, 1H) ppm, 13
J=3 Hz)
C NMR (75 MHz, DMSOꢀd6): δ=43.4, 120.9, 121.9, 123.5, 123.8, 126.7,
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127.5, 127.6, 128.4, 129.6, 130.6, 131.9, 131.9, 132.9, 133, 138.5, 145.9, 147.6, 150.8, 156.4, 165.9.
HRMS (ESIꢀ): calcd. for HRMS (ESIꢀ): calcd. for C21H14N4O8SCl [M + Cl]ꢀ 517.0243; found 517.0229.
4-(2-(Buta-1,3-dien-2-yloxy)phenyl)-1,5-benzodiazepin-2-one 11: To a solution of 4ꢀ(2'ꢀhydroxypheny1)ꢀ
1,5ꢀbenzodiazepinꢀ2ꢀone 1 (0.25g, 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 reaction mixture was stirred for 10 to 15 min before
the addition of acryloyl chloride (0.09 ml, 1.1 mmol, 1.1 equiv.). The mixture was stirred for 30 mn, and
THF is then removed under pressure, and purified by flash column chromatography on silica gel
(Cyclohexane/EtOAc from 100:0 to 80:20) to obtained the titled compound (0.228 g, 75% yield) as
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white solid. mp = 195ꢀ197 °C. IR (ATR): νmax
:
3050(NH), 1736 (CO), 1670(CN), 1614(CO). 1H NMR (300
3.39(s, 2H), 6.22(dd,
MHz, CDCl3): δ =
), 6.45(dd,
),
J=15 Hz , J=9 Hz, 1H
J=12 Hz , J=3 Hz, 1H
6.55(dd,
), 7.44 (
(
,
J=15 Hz , J=3 Hz, 1H
d, J = 9 Hz, 1H), 7.45ꢀ7.99 m, 2H), 8.09ꢀ8.12(m, 2H) 8.17(d,
, 10.08(s, 1H) ppm,
J=3 Hz, 1H)
13C NMR (75 MHz, DMSOꢀd6): δ= 34.9, 42.2, 118.5, 119.3, 119.6,
126.8, 127.8, 131.8, 134.1, 134.9, 135, 137.3, 144.6, 145.1, 145.2, 159.8, 162.6, 165.7, 167.1 ppm.
HRMS (ESI+): calcd. for C18H15N2O3 [M+H]+ 307.1083; found 307.1075.
Procedure for the detection of biothiols on TLC plates
5 ꢁL of a ~2 mM solution of the corresponding fluorogenic probe (10 or 11) in THF were dropped on
the TLC plate. Then, 9 ꢁL (2 times at interval of 10 min) of a ~10 mM solution of the corresponding
amino acid (except BSA whose concentration was 50 ꢁM) in PBS 7.4 were dropped on the probe spot.
After 10 min, the spot was dried under air flow, and the TLC plate subsequently eluted in
EtOAC/cyclohexane (1:1), and then visualized under visible and UV light at a wavelength of 365 nm.
Acknowledgment: This work was also partially supported by Rouen University, INSA Rouen, Rouen
University, the Centre National de la Recherche Scientifique (CNRS), Region HauteꢀNormandie
(CRUNCh network),and the Labex SynOrg (ANRꢀ11ꢀLABXꢀ0029). The authors are grateful to Mrs
Amna Benzarti and Miss Nadia Msaddek, NMR service at the Faculty of Monastir, University of
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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 Xꢀray diffraction analyses and Dr. Carole KarakasyanꢀDia for helpful discussions.
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Supporting Information Available: H and C NMR spectra, and photophysical data for all new
compounds, Xꢀray crystallographic data (CIF files) for compounds 1 and 9. This material is available
free of charge via the Internet at http://pubs.acs.org.
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