Design, synthesis and investigation of water-soluble hemi-indigo photoswitches for bioapplications

Article abstract of DOI:10.3762/bjoc.15.275

A series of hemi-indigo derivatives was synthesized and their photoswitching properties in aqueous medium were studied. The dimethoxy hemi-indigo derivative with the best photochromic performance in water was identified as a promising platform for the dev

Full text of DOI:10.3762/bjoc.15.275

Design, synthesis and investigation of water-soluble
hemi-indigo photoswitches for bioapplications
Daria V. Berdnikova
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2019, 15, 2822–2829.
Department Chemie–Biologie, Organische Chemie II, Universität
Siegen, Adolf-Reichwein-Str. 2, 57076 Siegen, Germany
doi:10.3762/bjoc.15.275
Received: 31 August 2019
Accepted: 07 November 2019
Published: 22 November 2019
Email:
Daria V. Berdnikova - berdnikova@chemie-bio.uni-siegen.de
This article is part of the thematic issue "Molecular switches".
Guest Editor: W. Szymanski
Keywords:
hemi-indigo; molecular switches; photochromism; photoswitching;
visible light; water solubility
© 2019 Berdnikova; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
A series of hemi-indigo derivatives was synthesized and their photoswitching properties in aqueous medium were studied. The
dimethoxy hemi-indigo derivative with the best photochromic performance in water was identified as a promising platform for the
development of photoswitchable binders for biomolecules. The synthetic approach towards the introduction of the alkylamino
pendant to the dimethoxy hemi-indigo core was developed that allowed to obtain an RNA-binding hemi-indigo derivative with
photoswitchable fluorescent properties.
Introduction
The application of organic photochromes in biological systems nowadays the development of photopharmacology is based
is fraught with their poor solubility and reduced photo- mainly on azobenzene chemistry [10,11] and, therefore, finding
switching efficiency in aqueous medium. In many cases, ap- of new biocompatible photochromes with complementary prop-
proaches to improve the water solubility by chemical modifica- erties is highly desirable to speed up the progress in this impor-
tion of the photochromic scaffolds are not straightforward tant field. In this context, an emerging class of hemi-indigo
because the introduction of substituents often interferes with the photoswitches attracted special attention [12-17]. Despite the
desired photochemical properties. Along these lines, special fact that the hemi-indigo dyes are known for more than
efforts have been devoted to design, for example, water-soluble 100 years [18], their photochemical properties are still underex-
derivatives of spiropyran [1-3], azobenzene [4,5], diarylethene plored and no targeted studies on their photoswitching in
[6-8], or chromene [9] that keep efficient photochromism in aqueous media were performed. The hemi-indigo scaffold
aqueous medium. Although a significant progress has been exists in two forms that can be photoswitched reveresibly. In
made in the development of water-soluble photochromes, there most cases, the Z-isomer of hemi-indigo is thermodynamically
is still an emerging search for new types of photochromic com- stable whereas the E-isomer is metastable. However, if the
pounds for applications in biological systems. In particular, indoxyl nitrogen is substituted with alkyl or aryl groups, both
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isomers of hemi-indigo have very close energies and none of [13]. All compounds 1a–c were obtained in good yields as pure
them is clearly preferred thermodynamically [13]. The absorp- Z-isomers as supported by the NMR data (Figures S5–S13 in
tion spectrum of the E-isomer is bathochromically shifted rela- Supporting Information File 1).
tive to the one of the Z-isomer. Depending on the substitution
pattern, the thermal lifetimes of metastable E-isomers at 25 °C
vary from hours to days and sometimes even years [12-14].
Remarkably, for sterically hindered hemi-indigo derivatives,
thermal lifetimes of the metastable states beyond 3000 years
have been achieved [14]. Unlike most of the widely applied
photochromes (spiropyrans, spirooxazines, chromenes,
dithienylethenes, etc.), both forms of hemi-indigo absorb in the
visible light region. Therefore, photochemical switching does
not require the use of the UV light, which is of high importance
for biological applications.
Scheme 1: Synthesis of hemi-indigo derivatives Z-1a–c.
Herein, the synthesis and adjustment of the substitution pattern
of hemi-indigo derivatives for the efficient photoswitching in
aqueous medium are described. Detailed characterization of the
Introduction of an alkylamino substituent to
photoinduced isomerization of hemi-indigo derivatives in water the hemi-indigo scaffold
is provided. Additionally, synthetic peculiarities of the introduc- Based on the data on photoswitching in water (vide supra), the
tion of an RNA-affine alkylamino substituent to the hemi- dimethoxy-substituted hemi-indigo Z-1c was selected as a core
indigo scaffold are discussed.
structure for the design of RNA binders with photoswitchable
properties [12]. To increase the solubility in aqueous medium
and potential RNA-binding properties, the dimethylamino-
propyl substituent [19] was introduced to hemi-indigo Z-1c.
Results and Discussion
Synthesis of hemi-indigo derivatives Z-1a–c
The synthesis of hemi-indigo derivatives Z-1a–c with different Two synthetically straightforward approaches of the alkyl-
substitution patterns of the phenyl ring was performed through amino group introduction were considered: (i) N-alkylation of
the aldol condensation of indoxyl-3-acetate with the corre- the indoxyl core and (ii) O-alkylation of the dimethoxyphenyl
sponding benzaldehydes under alkaline conditions (Scheme 1) residue (Scheme 2).
Scheme 2: Synthetic routes to alkylamino-substituted dimethoxy hemi-indigo Z-1c.
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Surprisingly, compound 3 (method I) could not be obtained due Z-isomer with 24% yield (Scheme 2) [12]. Importantly, the syn-
to the cleavage of the C–C double bond in the course of the thesis of Z-2 required milder conditions and shorter reaction
reaction followed by extensive destruction of the heterocyclic times than that of derivatives Z-1a–c. Thus, the use of the
fragment. Variation of the reaction conditions, e.g., reduction of water/methanol mixture as a solvent, heating and extended reac-
the reaction temperature and time, changing the ratio of the tion times of more than 2 h resulted in the destruction of the
reactants and addition of NaI as a catalyst, did not suppress this desired product Z-2. At the same time, performing the reaction
decomposition to a significant extent. A possible reason for this at room temperature in pure ethanol allowed to increase the
side process is the reactivity of the double bond carbon atom yield of Z-2 and to reduce the number of side-products. Purifi-
(Michael acceptor) [20]. The intramolecular nucleophilic attack cation of hemi-indigo Z-2 by conventional column chromatog-
of the introduced alkylamino group can possibly lead to the raphy was not efficient. However, pure product Z-2 could be
immediate double-bond cleavage in 3. This results in formation obtained by gel filtration chromatography on sephadex
of unstable indoxyl that undergoes further destruction and vera- (MeOH); the isolated compound Z-2 is stable in its free base
traldehyde that is detected in the reaction mixture by NMR. form whereas its hydrochloride salt slowly decomposes.
This assumption is supported by the observation that only one
Optical properties and photoswitching in
hemi-indigo derivative bearing an alkylamino substituent of a
shorter length on the indoxyl N atom has been reported so far aqueous medium
[20]. Hemi-indigo derivatives Z-1a–c display intense long-wave-
length absorption bands, whose maxima are clearly dependent
Modification of the phenyl ring by method II was successful on the strength of the electron-donating substituent in the 4-po-
and allowed to obtain the desired hemi-indigo 2 as a pure sition of the phenyl ring (Figure 1, Table 1). Thus, the exchange
Figure 1: Photoswitching of hemi-indigo derivatives: (A) Z-1a, c = 20 μM in H2O with 10% (v/v) DMSO, λex = 420 nm; (B) Z-1b, c = 20 μM in H2O with
2% (v/v) EtOH, λex = 470 nm (forward reaction) and 590 nm (backward reaction); (C) Z-1c, c = 20 μM in H2O with 2% (v/v) EtOH, λex = 470 nm
(forward reaction) and 590 nm (backward reaction); (D) Z-2, c = 15 μM in H2O, λex = 470 nm (forward reaction) and 590 nm (backward reaction),
20 °C. Spectra of the initial Z-isomers: black; PSS420: orange; PSS470: blue; PSS590: red.
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Beilstein J. Org. Chem. 2019, 15, 2822–2829.
Table 1: Photochemical and photophysical properties of hemi-indigo derivatives 1a–c and 2 in water.
Species
λabs (Z)/nm ε (Z)/
λabs (E)/
nma
ε (E)/
L mol−1
cm−1a
PSS470/
(% Z/E)a
PSS590/
(% Z/E)a
ΦZ-E/ΦE-Z / ΔG*/
t1/2 25 °Сd
L mol−1
10−2 b
kcal
cm−1
mol−1 c
1ae
1b
1c
2
521
479
479
478
478
26039
11922
12086
10549
10456
n.d.f
508
515
515
514
n.d.f
n.d.f
n.d.f
n.d.g
93/7
97/3
97/3
n.d.f
n.d.f
26.5
26.2
26.1
23.7
n.d.f
47 d
31 d
25 d
11 h
6727
7127
6368
6289
28/72
21/79
24/76
20/80
3.8/n.d.g
2.6/0.2
2.4/0.1
2.7/0.2
2h
aCalculated according to Fischer [21]. bPhotoisomerization quantum yields of the forward ΦZ-E (at 470 nm) and backward ΦE-Z (at 590 nm) reactions.
cFree activation enthalpies for the thermal E–Z isomerization. dHalf-lifes of the E-form at 25 °C. eIn water containing 10% (v/v) DMSO. fCompound
shows very weak photochromism in aqueous medium. gThe backward switching was not complete due to precipitation of the compound after 2 h of ir-
radiation. hThe data were obtained in aqueous 10 mM Na-phosphate buffer containing 0.1 M NaCl, pH 7.0 [12].
of the 4-dimethylamino group in Z-1a for a 4-methoxy group in pattern is unfavorable for photoswitching in aqueous medium.
Z-1b resulted in a significant blue shift of the absorption Thus, a higher content of organic co-solvents (20–30% of
maximum (Δλ = 42 nm). Notably, the introduction of a second DMSO, DMF or THF) or/and the presence of triethylamine was
methoxy group to the 3-position of the phenyl ring in Z-1c did required to stimulate the photoswitching of the reported
not shift the absorption maximum and just slightly affected the compounds with a 4-amino group in the phenyl ring [13].
extinction (Table 1). Hemi-indigo derivatives Z-1a–c are not Considering the limitations imposed on the nature and
fluorescent in aqueous solution.
content of organic co-solvents used in biological studies, the
dimethylamino derivative Z-1a was excluded from further
To assess the potential applicability of hemi-indigo derivatives studies.
Z-1a–c in biological systems, photoswitching of these com-
pounds was tested in aqueous medium (Scheme 3). The forward In contrast, mono- and dimethoxy-substituted hemi-indigo de-
reaction was performed upon irradiation at 360 (UV), 420 nm rivatives Z-1b and Z-1c showed pronounced spectral changes
(violet), 470 nm (blue) and 520 nm (green) light (Figure 1 and upon irradiation indicating an efficient Z–E isomerization of the
Figures S1 and S2 in Supporting Information File 1).
C–C-double bond (Figure 1B and Figure 1C). The most com-
plete Z–E conversion for both compounds Z-1b and Z-1c was
Surprisingly, almost no switching of the dimethylamino-substi- achieved upon irradiation with blue light (470 nm) (cf. Figures
tuted hemi-indigo Z-1a was observed in water with 10% S1 and S2, Supporting Information File 1). The photoreactions
DMSO, i.e., only irradiation with violet light (420 nm) led to proceeded rather fast and the photostationary state PSS470 was
the residual isomerization (Figure 1A). Additionally, the hemi- reached within 2.5 min for compound Z-1b and within 3.0 min
indigo Z-1a was hardly soluble in aqueous medium and rather for compound Z-1c. The backward E–Z conversion from
fast precipitation took place even in the presence of the co-sol- PSS470 was performed by irradiation with 590 nm (amber) light
vent. The comparison with the reported data on Z-1a [13] and and occurred much slower (Table 1). In the case of
related hemi-indigo derivatives containing a 4-amino group in monomethoxy derivative E-1b, the backward reaction from
the phenyl ring [13] allowed to conclude that this substitution PSS470 proceeded successfully during ca. 2 h of irradiation after
Scheme 3: Photoswitching of hemi-indigo derivatives.
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which the isosbestic point was lost and the absorption intensity absorption maxima of both, the Z- and E-forms, the extent of
started decreasing due to slow precipitation of the compound conversion in PSSs, the photoisomerization quantum yields as
from the aqueous solution (Figure 1B). The presence of the well as the half-lifes of the photoinduced forms appeared to be
second methoxy group ensured a better stability of aqueous almost independent of the presence of the alkylamino substitu-
solutions of the dimethoxy derivative Z-1c. In this case, the ent. Interestingly, a comparison with the data obtained for Z-2
backward E–Z isomerization of E-1c from PSS470 took place in aqueous 10 mM Na-phosphate buffer containing 0.1 M NaCl,
within 5 h resulting in almost complete restoration of the initial pH 7.0 [12], showed that the increase in the ionic strength of the
absorbance of Z-1c in the PSS590 (Figure 1C). Investigation of medium resulted in a drastic decrease of the half-life of the pho-
the photostationary mixtures by fluorescence spectroscopy toinduced form E-2 whereas other characteristics remained
revealed that the photoinduced isomers E-1b and E-1c are not almost unaffected (Table 1). This indicates that the highly ionic
fluorescent in aqueous medium. The analysis of the isomeric medium reduces the energy barrier in the ground state that is re-
compositions of the photostationary states was performed by sponsible for the rate of thermal E–Z isomerization pointing out
the Fischer method [21] because NMR-spectroscopic analysis the importance of the Coulomb interactions between hemi-
was precluded by insufficient solubility or/and possible aggre- indigo and buffer components. A possible explanation of this
gation at higher concentrations. Thus, the Fischer method observation can be provided by the comparison with struc-
allowed to calculate the absorption spectra of pure E-isomers of turally related hemi(thio)indigo dyes [22]. Thus, in the case of
1b and 1c in water (Figure 2) as well as to evaluate the extent of hemi(thio)indigo, the energy maximum in the ground state cor-
the Z–E conversion in PSS470 and PSS590 (Table 1).
responds to the 90° rotation about the central double bond re-
sulting in formation of a state with biradical-like character that
The dimethoxy derivative Z-1c showed better Z–E conversion is polarized along the molecule’s long axis [22]. The close
in PSS470 and a larger difference between the absorption structural similarity allows to expect a similar character of the
maxima of the Z- and E-forms. At the same time, the introduc- transition state for the hemi-indigo derivatives. Therefore, a
tion of the second methoxy group to the phenyl ring resulted in highly ionic medium can stabilize the transition state of the
a decrease of the Z–E isomerization quantum yield and reduced hemi-indigo leading to the decrease of the energy barrier be-
the thermal half-life of E-1c in comparison to E-1b (Table 1). tween Z- and E-isomers and, therefore, reducing the half-life of
Nevertheless, the dimethoxy-substituted hemi-indigo Z-1c was the E-form. However, further studies are required to provide
selected as a core structure for the design of photoswitchable detailed explanation of this effect.
RNA binders due to its higher conversion and better solubility
in water.
Recently, a proof-of-principle for the application of hemi-
indigo derivative Z-2 as a binder for the human immunodefi-
The introduction of the alkylamino group provided compound ciency virus type 1 (HIV-1) RNA with photoswitchable fluores-
Z-2 with much better solubility in water. At the same time, the cent properties was provided [12]. It was shown that hemi-
presence of the alkylamino substituent only slightly influenced indigo Z-2 associates with the regulatory elements of HIV-1
the photochemical and photophysical characteristics of the genome RNA with high affinity (Kb ≈ 105 M−1) while keeping
hemi-indigo Z-2 in comparison with the parent compound Z-1c its photoswitching properties. Both, the initial Z-2 and photoin-
(Figure 1D, Figure 2C, Table 1). Thus, the positions of the duced E-2 forms remain bound to RNA. Most notably, the
Figure 2: Absorption spectra of the Z-isomer (black), two photostationary states obtained upon irradiation with 520 nm (red) and 470 nm (blue) light
for (A) 1b, (B) 1c, (C) 2 in water, c = 20 μM, 20 °C. Grey dashed line represents the spectra of the corresponding E-isomers calculated by the Fischer
method.
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Beilstein J. Org. Chem. 2019, 15, 2822–2829.
interaction of Z-2 with HIV-1 RNA produces a remarkable Cary 100 Bio two-beam spectrophotometer and a Specord 600
light-up effect whose extent depends on the particular sequence (Analytik Jena AG) diode-array spectrophotometer. Fluores-
of RNA. Photoswitching of the RNA-bound hemi-indigo Z-2 to cence spectra were recorded on a Cary Eclipse spectrofluo-
the E-form results in emission quenching. The ON–OFF fluo- rimeter. Optical spectroscopy measurements were performed in
rescence switching of Z-2–RNA complexes can be performed thermostated quartz sample cells of 10 mm pathlength. Prepara-
reversibly by repeated irradiation with blue (470 nm) and amber tion and handling of the solutions were carried out under red
(590 nm) light.
light. Photochemical reactions were performed using the
following LED light sources: LUMOS (360 nm); Roithner
H2A1-H420 130 mW (420 nm); Roschwege HighPower-LED
Conclusion
To sum up, hemi-indigo derivatives with different substitution Blau (470 nm); Roschwege HighPower-LED Grün (520 nm);
patterns in the phenyl ring were synthesized and their photo- Roschwege HighPower-LED Amber (590 nm).
chemical behavior in aqueous medium was studied. The pres-
ence of a methoxy group in the 4-position of the phenyl ring Synthesis
was identified as a necessary condition for the efficient photo- The synthesis and characterization of hemi-indigo derivative
switching of hemi-indigo in water. At the same time, the pres- Z-2 are described in detail in [12].
ence of a strong electron-donating dimethylamino group at this
position is unfavorable for the photoswitching in water. It was General procedure for the synthesis of hemi-indigo
also shown that the introduction of a second methoxy group in derivatives Z-1a–c
the 3-position of the phenyl ring improves the water solubility Under argon gas atmosphere, a solution of indoxyl-3-acetate
of the photoswitch and increases the red shift of the absorption (200 mg, 1.14 mmol) in aqueous NaOH (1.5 M, 6.2 mL,
maximum of the E-isomer. As a further step, the synthetic ap- degassed) was heated at 100 °C for ca. 15 min. Then, the mix-
proach towards the attachment of the RNA-affine alkylamino ture was cooled to 0 °C and a solution of the corresponding
substituent was developed. Overall, the hemi-indigo derivatives aldehyde in 1–2 mL MeOH (Ar degassed) was added upon
were introduced as promising photoswitches for aqueous media vigorous stirring (for compound Z-1a: 4-(dimethylamino)benz-
possessing valuable properties for bioapplications.
aldehyde (170 mg, 1.14 mmol); for compound Z-1b: p-anisalde-
hyde (155 mg, 1.14 mmol); for compound Z-1c: veratraldehyde
(189 mg, 1.14 mmol)). After the addition of the aldehyde, the
mixture was warmed to ambient temperature and stirred for
Experimental
Materials and equipment
Reagents and solvents were obtained from commercial sources 3 days. Then, the mixture was neutralized with 1 M aq HCl and
(Acros, Merck, Fischer) and used as received. Reactions were extracted with EtOAc. The combined organic layers were dried
monitored on POLYGRAM® SIL G/UV254 (Macherey-Nagel) with Na2SO4 and the solvent was removed in vacuo. The ob-
TLC plates with detection by UV light irradiation (254 nm or tained solid was redissolved in EtOH and filtered to remove the
366 nm). Column chromatography was performed on insoluble precipitate of indigo side-product. After filtration, the
Sephadex® columns. 1H NMR and 13C NMR spectra were re- solvent was partially removed and the pure Z-isomer of the cor-
corded on a JEOL ECZ 500 spectrometer at 25 °C using 5 mm responding product was crystallized at −20 °C.
tubes. Chemical shifts were determined with accuracy of
0.01 ppm and 0.1 ppm for 1H and 13C spectra, respectively, and (Z)-2-(4-(Dimethylamino)benzylidene)indolin-3-one
are given relative to the residual signal of the solvent that was (Z-1a)
used as internal standard (DMSO-d6: δH = 2.50 ppm, δC = Deep violet needles, yield 86% (259 mg, 0.98 mmol); mp
39.5 ppm). Spin–spin coupling constants for the proton spectra 232–234 °С (lit. [13]: 235–236 °С); Rf 0.67 (hexane/EtOAc 1:1,
were determined with accuracy of 0.2 Hz. The proton NMR v/v); 1H NMR (500 MHz, DMSO-d6) δ 3.00 (s, 6H, H-17), 6.64
signal assignments were performed using COSY and ROESY (s, 1H, H-10), 6.78 (d, J = 9.0 Hz, 2H, H-13, H-15), 6.88 (ddd,
2D NMR techniques. The carbon NMR signal assignments J = 7.8, 7.0, 0.7 Hz, 1H, H-5), 7.14 (d, J = 8.1 Hz, 1H, H-3),
were performed by means of HSQC and HMBC 2D NMR tech- 7.47 (ddd, J = 8.3, 7.1, 1.3 Hz, 1H, H-4), 7.55 (d, J = 8.3. Hz,
niques. Mass spectra (ESI) were recorded on a Finnigan LCQ 1H, H-6), 7.61 (d, J = 8.8 Hz, 2H, H-12, H-16), 9.55 (s, 1H,
Deca mass spectrometer. Elemental analysis was performed H-1) ppm; 13C NMR (126 MHz, DMSO-d6) δ 39.7 (2C, C-17),
with a HEKAtech EUROEA combustion analyser by Mr. 112.1 (2C, C-13, C-15), 112.5 (1C, C-3), 112.6 (1C, C-10),
Rochus Breuer (Universität Siegen, Organische Chemie I). 119.1 (1C, C-5), 120.5 (1C, C-7), 121.3 (1C, C-11), 123.7 (1C,
Melting points were measured with a BÜCHI 545 (BÜCHI, C-6), 131.72 (2C, C-12, C-16), 131.68 (1C, C-9), 135.3 (1C,
Flawil, CH) melting point apparatus in open capillaries and are C-4), 150.3 (1C, C-14), 153.3 (1C, C-2), 185.2 (1C, C-8); Anal.
uncorrected. Electronic absorption spectra were measured on a calcd for C17H16N2O: C, 77.25; H, 6.10; N, 10.60; found: C,
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Beilstein J. Org. Chem. 2019, 15, 2822–2829.
77.05; H, 6.13; N, 10.39 %; ESIMS (MeOH, m/z): 263 Skłodowska-Curie actions (MSCA), under grant agreement No
[Z-1a − H]−, 264 [Z − 1a]+, 265 [Z-1a + H]+.
749788 – PHOTORNA. I thank Prof. Dr. Heiko Ihmels
(Universität Siegen, Germany) for fruitful discussions and valu-
able advices.
(Z)-2-(4-Methoxybenzylidene)indolin-3-one (Z-1b)
Brownish-golden powder, yield 60% (172 mg, 0.68 mmol); mp
180–181 °С (lit. [20]: 180–181 °С); Rf 0.75 (hexane/EtOAc 1:1,
v/v); 1H NMR (500 MHz, DMSO-d6) δ 3.82 (s, 3H, H-17), 6.65
(s, 1H, H-10), 6.90 (t, , J = 7.8 Hz, 1H, H-5), 7.04 (d, J =
8.8 Hz, 2H, H-13, H-15), 7.14 (d, J = 8.1 Hz, 1H, H-3), 7.51
(ddd, J = 8.4, 7.1, 1.1 Hz, 1H, H-4), 7.57 (d, J = 7.6 Hz, 1H,
H-6), 7.71 (d, J = 8.8 Hz, 2H, H-12, H-16), 9.68 (s, 1H, H-1)
ppm; 13C NMR (126 MHz, DMSO-d6) δ 55.3 (1C, C-17), 110.5
(1C, C-10), 112.6 (1C, C-3), 114.6 (2C, C-13, C-15), 119.5 (1C,
C-5), 120.2 (1C, C-7), 123.9 (1C, C-6), 126.6 (1C, C-11), 131.7
(2C, C-12, C-16), 133.1 (1C, C-9), 136.0 (1C, C-4), 153.9 (1C,
C-2), 159.6 (1C, C-14), 186.0 (1C, C-8) ppm); Anal. calcd for
C16H13NO2: C, 76.48; H, 5.21; N, 5.57; found: C, 76.31 H,
5.15; N, 5.50 %; ESIMS (MeOH, m/z): 250 [Z-1b − H]−.
ORCID® iDs
Daria V. Berdnikova - https://orcid.org/0000-0002-0787-5753
Preprint
A non-peer-reviewed version of this article has been previously published
as a preprint doi:10.3762/bxiv.2019.95.v1
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(Z)-2-(3,4-Dimethoxybenzylidene)indolin-3-one
(Z-1c)
Orange crystals, yield 66% (211 mg, 0.75 mmol); mp
191–192 °С; Rf 0.56 (hexane/EtOAc 1:1, v/v); 1H NMR
(500 MHz, DMSO-d6) δ 3.82 (s, 3H, H-18), 3.85 (s, 3H, H-17),
6.66 (s, 1H, H-10), 6.91 (t, J = 7.8 Hz, 1H, H-5), 7.06 (d, J =
8.4 Hz, 1H, H-15), 7.14 (d, J = 8.1 Hz, 1H, H-3), 7.29 (d, J =
2.0 Hz, 1H, H-12), 7.35 (dd, J = 8.7, 2.0 Hz, 1H, H-16), 7.51
(ddd, J = 8.3, 6.9, 1.1 Hz, 1H, H-4), 7.58 (d, J = 7.6 Hz, 1H,
H-6), 9.66 (s, 1H, H-1) ppm; 13C NMR (126 MHz, DMSO-d6)
δ 55.6 (1C, C-18), 55.7 (1C, C-17), 111.1 (1C, C-10), 112.0
(1C, C-15), 112.7 (1C, C-3), 113.8 (1C, C-12), 119.6 (1C, C-5),
120.4 (1C, C-7), 123.3 (1C, C-16), 123.9 (1C, C-6), 126.8 (1C,
C-11), 133.3 (1C, C-9), 136.0 (1C, C-4), 148.9 (1C, C-14),
149.5 (1C, C-13), 154.0 (1C, C-2), 186.0 (1C, C-8) ppm; Anal.
calcd for C17H15NO3: C, 72.58; H, 5.37; N, 4.98; found C,
72.80; H, 5.27; N, 4.89 %; ESIMS (MeOH, m/z): 280
[Z-1c − H]−.
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J. Am. Chem. Soc. 2017, 139, 15060–15067.
Supporting Information
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Supporting Information File 1
Additional spectral data, detailed description of the
experiments performed, NMR of compounds Z-1a–c and
LED characteristics.
[https://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-15-275-S1.pdf]
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Acknowledgements
This project has received funding from the European Union’s
Horizon 2020 research and innovation programme, Marie
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