Regiospecific Photocyclization of Mono- and Bis-Styryl-Substituted N-Heterocycles: A Synthesis of DNA-Binding Benzo[c]quinolizinium Derivatives

Article abstract of DOI:10.1021/acs.joc.6b01695

Regiospecific C-N photocyclization of mono- and bis-styryl-substituted N-heterocycles was investigated. We demonstrated that the C-N regiospecificity of the photoinduced electrocyclization is a general feature of ortho-styryl-substituted N-heterocycles comprising one and two nitrogen atoms. This phototransformation provides a straightforward synthesis of the pharmaceutically important benzo[c]quinolizinium cation and its aza-analogues. Noticeably, bis-styryl derivatives undergo only one-fold cyclization with the second styryl fragment remaining uninvolved in the cyclization process. Photocyclization products of monostyryl derivativatives intercalate into calf thymus DNA (ct DNA), whereas photocyclization products of bis-styryl derivativatives possess a mixed binding mechanism with ct DNA. The results can be used for development of novel DNA-targeting chemotherapeutics based on benzo[c]quinolizinium derivatives.

Full text of DOI:10.1021/acs.joc.6b01695

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Article
Regiospecific photocyclization of mono- and bis-styryl substituted N-
heterocycles: A synthesis of DNA-binding benzo[c]quinolizinium derivatives
Tseimur M. Aliyeu, Daria V. Berdnikova, Olga A Fedorova,
Elena N. Gulakova, Christopher Stremmel, and Heiko Ihmels
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b01695 • Publication Date (Web): 01 Sep 2016
Downloaded from http://pubs.acs.org on September 6, 2016
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Regiospecific photocyclization of mono- and bis-styryl
substituted N-heterocycles: A synthesis of DNA-binding
benzo[c]quinolizinium derivatives
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Tseimur M. Aliyeu†‡, Daria V. Berdnikova*†‡, Olga A. Fedorova†, Elena N. Gulakova†,
Christopher Stremmel‡, and Heiko Ihmels‡
† A. N. Nesmeyanov Institute of Organoelement Compounds of Russian Academy
of Sciences, 28 Vavilova str., 119991 Moscow, Russia
‡ Universität Siegen, Department Chemie-Biologie, Organische Chemie II, 57068
Siegen, Germany
berdnikova@chemie-bio.uni-siegen.de; daria@ineos.ac.ru
Abstract
Regiospecific C–N photocyclization of mono- and bis-styryl substituted N-heterocycles was
investigated. We demonstrated that the C–N regiospecificity of the photoinduced electrocyclization
is a general feature of ortho-styryl substituted N-heterocycles comprising one and two nitrogen
atoms. This phototransformation provides a straightforward synthesis of pharmaceutically important
benzo[c]quinolizinium cation and its aza-analogues. Noticeably, bis-styryl derivatives undergo only
one-fold cyclization with the second styryl fragment remaining uninvolved in the cyclization
process. Photocyclization products of mono-styryl derivativatives intercalate into calf thymus DNA
(ct DNA), whereas photocyclization products of bis-styryl derivativatives possess a mixed binding
mechanism with ct DNA. The results can be used for development of novel DNA-targeting
chemotherapeutics based on benzo[c]quinolizinium derivatives.
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Introduction
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Benzo[c]quinolizinium derivatives represent a pharmacologically important class of heteroaromatic
compounds that is applied in clinical practice.1 In particular, benzo[c]quinolizinium (often referred
to as MPBs) drugs are used as pharmacological chaperons2 that promote folding and channel
activation of the mutant CFTR protein (cystic fibrosis transmembrane conductance regulator) in the
treatment of mucoviscidosis.3 As efficient CFTR activators benzo[c]quinolizinium compounds
produce a relaxing effect on tracheal4 and aortic5 smooth muscle cells, thus inducing
bronchodilation and vasorelaxation. Because of these favorable properties a range of
benzo[c]quinolizinium derivatives has been patented for the use in the treatment of diseases that are
linked to smooth muscle cell constriction.6 In addition, DNA-binding properties of
benzo[c]quinolizinium ions7 as well as their inhibitory activity for protein kinase CKII8 make them
promising lead structures for the development of novel anticancer chemotherapeutic agents.
The first synthesis of the benzo[c]quinolizinium system was performed in 1958 by Glover and
Jones from cyanoquinolines in three steps.9 Later, Fozard and Bradsher obtained a series of
benzo[c]quinolizinium derivatives by thermal cyclization of cis-2′-chloro-2-stilbazoles.10 Arai et al.
developed a photochemical approach towards cyclization of chloro-substituted stylbazoles.11
Modified Ca2+-assisted thermal cyclization of halogenated phenylazopyridine and related Schiff
bases was applied for the synthesis of 5-aza, 6-aza, and 5,6-diaza analogues of
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benzo[c]quinolizinium.12 Another approach to synthesize
a
family of 5,6-diaza-
benzo[c]quinolizinium compounds is based on proton-catalyzed cyclization of 2-
(arylazo)pyridines.13 A series of substituted benzo[c]quinolizinium derivatives was prepared by
condensation of 2-picolyllithium and ortho-halogenobenzonitrile with subsequent thermally
induced cyclization.3a Some benzo[c]quinolizinium derivatives can be obtained by a ring-closing
metathesis (RCM) reaction.14 More recently, a range of novel benzo[c]quinolizinium salts was
synthesized by interaction of α-oxoketene S,S-acetals with 2-methylquinolyllithium or 2,4-
dimethyl-6-methoxyquinolyllithium followed by BF3-assisted cycloaromatization.15 However, all
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the reported methods possess at least one of the following significant drawbacks, namely
performance of the reactions at high temperature, requirement of a catalyst (acid, Ca2+), need of
halogenation of the substrates at certain positions, or multi-step reaction sequences.
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We are developing regiospecific C–N photocyclization of hetarylphenylethenes resulting in the
formation of charged polycyclic heteroaromatics.16-21 In this reaction, a new C–N bond is formed
through the photoinduced electrocyclic ring closure followed by in situ oxidation of the resulting
dihydrohetarene intermediate by air oxygen. The process takes place at mild conditions at room
temperature, does not require the use of catalysts and allows to obtain fused polycyclic cations with
good yields. Recently, we have shown that the C–N photocyclization of 2-styrylpyridine21 and 2-
styrylquinolines19 leads to the efficient and selective formation of benzo[c]quinolizinium
derivatives. Notably, we performed the photogeneration of the DNA-binding 8,9-
dimethoxybenzo[c]quinolizinium derivative 6 as a key process in a five-component supramolecular
cascade. In this system, the light-controlled transport of the in situ modified ligand 6 between
cyclodextrin, duplex DNA, and cucurbituril was accomplished; thus demonstrating biocompatibility
of this reaction (Scheme 1).21
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Scheme 1. Photocyclization of mono-styryl derivatives 1a–1e and chemical structures of annelated
quinolizinium derivatives 6 and 7
Analysis of our previous data as well as the recent report of Budyka et al. on the photocyclization of
styrylbenzoquinolines22 led us to the assumption that the regioselective C–N bond formation in the
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photochemical cyclization may be a general chemical reactivity of ortho-styryl-substituted N-
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hetarenes containing donor substituents in the styryl residue. If that is the case, this simple reaction
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would open
a
straightforward synthesis of
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wide range of biologically active
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benzo[c]quinolizinium derivatives.
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As a proof of our hypothesis we describe herein the regiospecific C–N photocyclization of mono-
and bis-dimethoxystyryl-substituted N-heterocycles to the corresponding benzo[c]quinolizinium
derivatives (Schemes 1 and 2). The substrates 1a–1e and 3a, 3b were prepared by Knoevenagel
condensation of the corresponding methyl-substituted heterocycles with veratraldehyde in the
presence of KOBut in DMF (Scheme S1, Supporting information). The methoxy groups were
introduced because our previous studies showed that these substituents provide high efficiency of
the photocyclization.19 Since annelated quinolizinium ions represent important key structures for the
design of DNA-targeting ligands23 we particularly focused our attention on the interactions of the
photocyclization products with DNA.
Scheme 2. Photoreactions of bis-styryl derivatives 3a and 3b.
Results and discussion
Photocyclization of mono-styrylazines 1a–1e
The photocyclization reactions of mono-styryl derivatives 1a–1e (Scheme 1) were carried out in air-
saturated solutions in acetonitrile or water upon irradiation with direct or filtered light of a high-
pressure Hg vapor lamp; and the course of the photoreaction was monitored photometrically. Direct
irradiation of dimethoxystyryl derivatives of pyrazine 1a, pyridazine 1d and isoquinoline 1e in
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acetonitrile led to the appearance of new red-shifted absorption bands at 350–450 nm (Figures S1,
S4, S5, Supporting information). These bands were assigned to the photocyclization products 2a, 2d
and 2e by analogy to our previous reports.16-21 The regioselective formation of a new C–N bond in
all cases was unambiguously proven by the 1H NMR spectroscopic data based on the characteristic
downfield shifts of the aromatic proton signals that clearly indicate the formation of the
quinolizinium structure (Figures S11–S34, Supporting information). No products of C–C
cyclization were detected. The remarkable regiospecificity of this photoreaction is caused by the
significantly lower enthalpy of formation of the C−N cyclization product in comparison to that of
C−C cyclization product formation, as was described previously for 2-styrylquinoline derivatives.19
Moreover, no positional isomerism of the methoxy substituents was detected for photocyclization
products 2a, 2d, 2e, E-4a and E-4b. This means that formation of a new bond takes place only
between N and C6' atoms of the styrylheterocycles (Schemes 1 and 2). Considering that the
electrocyclization occurs from the Z-form of 1 and 3 the stability of different conformations of the
corresponding Z-isomers influences the structure of the resulting polycyclic product. Thus, in the
conformation of the Z-isomer that results N–C2' cyclization one of the methoxy groups in the
phenyl ring is directed towards the heterocyclic fragment. This arrangement, however, leads to
increased steric repulsion and destabilizes the corresponding conformation. On the other hand, in
the conformation of the Z-isomer that leads to N–C6' cyclization the steric interactions are
minimized so that the formation of a new bond between N and C6' atoms is energetically favored.
The mono-styryl derivatives 1b, 1c, 1d, the bis-styryl derivative 3b and all photocyclization
products 2a, 2d, 2e, E-4a and E-4b are novel compounds and were fully characterised by NMR
spectroscopy and HRMS.
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Photolysis of 1a, 1d and 1e in water under similar conditions resulted in formation of more intense
absorption bands of products 2a, 2d and 2e (Figure 1) as compared to the photoreaction in
acetonitrile. This fact points out higher efficiencies of the photocyclization in aqueous solution.
Optimization of the conditions revealed that in case of compound 1a the use of a cut-off filter (λ >
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290 nm) leads to an enhanced yield of photoproduct 2a. However, the removal of the short-
wavelength light increased the conversion time of 1a by ca. 2.7. Heteroaromatic compounds 2a, 2d
and 2e were successfully isolated as perchlorate salts in moderate yields (2a: 39%; 2d: 57%; 2e:
50%) by recrystallization from MeOH with addition of equimolar amount of HClO4.
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Figure 1. Spectral changes during the photolysis of 1a, 1d and 1e (c = 20 μM, water, high-pressure
Hg lamp, 20 °C): A: 1a, λ > 290 nm, 95 min; B: 1d, no filter, 16 min; C: 1e, no filter, 15 min.
In contrast, direct irradiation of styrylpyrimidine derivatives 1b and 1c in acetonitrile with led to
broad, almost shapeless spectra indicating extended photodecomposition that was confirmed by the
NMR-spectroscopic analysis of the photolysate (Figures S2, S3, S9, S10, Supporting information).
To improve the yield of the desired photoproducts we irradiated 1b and 1c in aqueous solution. The
absorption spectra obtained after photolysis in water revealed pronounced red-shifted bands in the
characteristic absorption range of the benzo[c]quinolizinium (Figure 2). Nevertheless, the isolation
of the products 2b and 2c from the photolysate was not successful. For this reason, the obtained
solutions were analyzed by HPLC (Figures S6 and S7, Supporting information). Unfortunately, the
complexity of the product mixtures, comprising at least four components with close retention times,
did not allow unambiguous determination of their composition. It was obvious, however, that even
if the desired products 2b and 2c were formed, their content in the complex mixtures was very low
and any attempts of their isolation had no preparative meaning. The most probable reason for this
observation is the photochemical instability of compounds 2b and 2c that – unlike 2a, 2d and 2e –
undergo side reactions or secondary photoreactions in the course of the photolysis. In particular, it
is known that pyrimidine derivatives possess low photostability and may undergo a [2+2]
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photocycloaddition reaction resulting in the formation of the intermolecular dimers.24 To check this
assumption a control experiment was performed with the photolytic mixture obtained after
irradiation of styrylpyrazine derivative 1a in water (λ > 290 nm) (Figure 1A). In this case only two
fractions were separated by HPLC with significantly different retention times (Figure S8,
Supporting information). The absorption spectra of the obtained fractions coincide well with the
absorption spectra of substrate 1a and its photocyclization product 2a. This observation confirmed
the low stability of pyrimidine derivatives during the photolysis in comparison to other mono-
styrylazines from the employed series.
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Figure 2. Spectral changes during the photolysis of 1b and 1c in water (c = 20 μM, high-pressure
Hg lamp, 20 °C): A: 1b, λ > 290 nm, 35 min; B: 1c, no filter, 15 min.
Photocyclization of bis-styrylazines 3a and 3b
Fused bis-styryl derivatives of pyrazine 3a and pyrimidine 3b, with both styryl moieties located in
the ortho-positions to the nitrogen atoms of the central azine ring are potentially capable of two-fold
C–N cyclization (Scheme 2). Two possible types of C–N electrocyclization products for 3a, 3b can
be suggested with only one or both styryl fragments involved in the cyclization yielding
corresponding mono- and dicationic heteroaromatics 4a, 4b and 5a, 5b. It should be noted that the
dimethoxystyryl fragment of monocationic species 4a and 4b can potentially exist in E- or Z-form.
Direct irradiation of the acetonitrile solutions of bis-styrylpyrazine 3a and bis-styrylpyrimidine 3b
under aerobic conditions resulted in the formation of the red-shifted absorption bands that indicate
the extension of a conjugated aromatic system in the course of the photoreaction (Figure 3). The
photolysate was purified by recrystallization from MeOH in the presence of HClO4. As a result,
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pure E-isomers of monocyclization products 4a, 4b were isolated as perchlorate salts with low to
moderate yields (E-4a: 25%; E-4b: 51%). Neither Z-isomers of 4a, 4b nor dicationic species 5a, 5b
were detected (Figure 4). Interestingly, irradiation of 3a and 3b with filtered light (λ = 405 nm for
3a or λ = 365 nm for 3b) did not lead to the formation of polycyclic products. The poor solubility of
3a and 3b in water did not allow us to test the photocyclization process in aqueous medium.
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Figure 3. Spectral changes during the photolysis of the bis-styryl derivatives in acetonitrile (c = 20
μM, unfiltered light of a high-pressure Hg vapor lamp, 20 °C): A: 3a, 30 min; B: 3b, 16 min.
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Figure 4. H NMR spectra (400 MHz, range of the aromatic and olefin bond protons) of bis-styryl
derivative E-3a (top) and its photocyclization product E-4a (bottom) in CD3CN. The signals of the
trans-double bonds are highlighted in blue. Dashed lines show shifting of the signals of the styryl
fragment protons of photoproduct E-4a in comparison to the ones of the substrate 3a.
The inhibition of the photoinduced E-Z-isomerization in 4a and 4b unambiguously points out the
presence of an alternative dominating relaxation pathway in the excited state. Indeed, compounds
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4a and 4b resemble cationic styryl dyes with a highly polar donor–acceptor structure that upon
photoexcitation in polar media readily undergo non-radiative relaxation through rotation about
single bonds and formation of twisted excited states.25 In such systems, E-Z-isomerization of the
C=C double bonds is usually significantly suppressed. Therefore, we assume that the absence of E-
Z-isomerization may be a consequence of the pronounced dipolar character of 4a, 4b that promotes
relaxation through the twisted excited states. However, the detailed investigation of the
photophysical behavior of 4a and 4b is beyond the scope of the present study.
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The exclusive formation of 4a and 4b in the E-form provides an explanation why two-fold
cyclization to 5a, 5b does not occur, because the cyclization can take place only from the Z-form of
a styrylheterocyclic species.19 Since the Z-isomers of 4a and 4b do not form, the cyclization process
cannot proceed further and stops on the monocyclization stage. An additional reason for the
impeded second cyclization may be the electrostatically unfavorable accumulation of two positive
charges within one six-membered ring in 5a and 5b.
DNA-binding properties of photocyclization products 2a, 2d, 2e
The photoproducts 2a, 2d and 2e possess characteristic features of DNA-intercalators, namely,
planar heteroaromatic structure with a permanent positive charge.26 To assess DNA-binding
properties of these compounds their interaction with calf thymus DNA (ct DNA) was examined by
spectrometric titrations. Thus, addition of ct DNA to the solutions of compounds 2a, 2d, and 2e
produced a strong hypochromic effect along with a pronounced red shift of the absorption of the
ligand that is indicative of a strong interaction with DNA (Figure 5A, Table 1). In all cases, an
isosbestic point is maintained during the titrations that indicates one almost exclusive binding
mode. Fitting of the binding isotherms obtained from the photometric titrations to the neighbor-
exclusion model27 gave the binding constants for the complexes of 2a, 2d, and 2e with ct DNA
(Table 1). The binding constant of 3-azabenzo[c]quinolizinium derivative 2a (Kb = 1.1 × 105 M-1) is
very close to the one reported for 8,9-dimethoxybenzo[c]quinolizinium 6 (Kb = 1.2 × 105 M-1)21
which can be explained by close structural resemblance of these compounds. At the same time, the
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DNA-binding affinity of structurally similar 1-azabenzo[c]quinolizinium derivative 2d is slightly
lower (Kb = 6.6 × 104 M-1). The binding constant of 2,3-dimethoxy-isoquinolinoquinolinium
derivative 2e (Kb = 4.6 × 105 M-1) is of the same order of magnitude as the one of the parent
compound 7 (Kb = 1.9 × 105 M-1).28 Overall, the values of the binding constants of ligands 2a, 2d,
and 2e with ct DNA are in good agreement with the reported data for DNA-intercalators of similar
structure and size. The fluorescence of 2a, 2d and 2e was efficiently quenched upon addition of ct
DNA with almost no changes in the positions of the emission maxima (Figure 5B, Table 1), which
usually indicates the photoinduced electron transfer (PET) reaction between the bound ligand and
the DNA bases, specifically the easily oxidized guanine residues.29 Complementary polarimetric
titrations revealed that in the presence of ct DNA the achiral ligands 2a, 2d and 2e display induced
circular dichroism (ICD) signals that resemble the long-wavelength absorption of the ligands in the
presence of DNA (Figure 5C). The tricyclic compounds 2a and 2d possess weak positive ICD
signals whereas the tetracyclic derivative 2e exhibits a strong bisignated ICD signal that may
indicate aggregation of 2e in the presence of DNA or two energetically close orthogonal transition
dipoles.30 In particular, the positive ICD signals result from an alignment of the transition dipole of
the ligands perpendicular to the long axis of the binding pocket, i.e. the direction of the transition
dipole of the DNA bases.30 At the same time, it may be assumed that the transition dipole moment
of the long-wavelength absorption band of the ligands 2a, 2d and 2e is essentially pointing along
their long-molecular axes, i.e. from the methoxy sustituents to the pyridinium unit (Scheme 1). As a
result, similarly as demonstarted for 7 already in detail,28 it can be deduced from the positive ICD
band that the ligands intercalate into DNA with their long molecular axes pointing almost
perpendicular relative to the long axis of the intercalation pocket.
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Figure 5. A: Spectrophotometric titration of ct DNA to 2a (A1, c2a = 50 μM, cDNA/c2a = 0–21); 2d
(A2, c2d = 50 μM, cDNA/c2d = 0–23); 2e (A3, c2e = 20 μM, cDNA/c2e = 0–24). B: Fluorimetric titration
of ct DNA to 2a (B1, c2a = 20 μM, cDNA/c2a = 0–59, λex = 418 nm); 2d (B2, c2d = 20 μM, cDNA/c2d =
0–57, λex = 396 nm); 2e (B3, c2e = 10 μM, cDNA/c2e = 0–14, λex = 410 nm). C: CD spectra of
mixtures of ct DNA (cDNA = 50 μM, in base pairs) with ligands 2a (C1), 2d (C2), 2e (C3) at ligand-
DNA ratio LDR = 0, 0.3, 0.6, 0.8, 1.0, 1.5. In all cases: BPE buffer (pH 7.0) with 2% v/v DMSO, T
= 20 °C.
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Table 1. Absorption and emission maxima of free and DNA-bound ligands 2a, 2d, 2e, E-4a, E-4b
and binding constants of their complexes with ct DNA in BPE buffer (pH 7.0) with 2% v/v DMSO
(for 2a, 2d, 2e) or 5% v/v DMSO (for E-4a, E-4b).
λabs / nm a
λfl / nm b
Kb / M-1
free
405
382
403
460
452
bound
415
free
470
463
442
456
547
bound
472
1.1 × 105 c
6.6 × 104 c
4.6 × 105 c
2a
2d
393
460
418
443
2e
d
E-4a
E-4b
477
500
-
475
550
b
5.0 × 105 e
a
Long-wavelength absorption maxima of free and DNA-bound ligands. Fluorescence maxima of
free and DNA-bound ligands. c Binding constant with ct DNA, obtained from the photometric data.
d Binding constant was not determined. e Average binding constant with ct DNA, obtained from the
fluorimetric data that reflects the combination of two binding modes. T = 20 °C.
To verify the proposed intercalative binding mode of the heteroaromatic photoproducts 2 with ct
DNA, flow-linear dichroism (LD) spectroscopic analysis30 was performed exemplarily with ligand
2e (Figure 6). The ct DNA without ligand gives a negative signal in the absorption region of the
DNA bases (Figure 6A) as a result of the perpendicular alignment of the transition dipole moment
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of the bases relative to the LD reference axis.30 The addition of ct DNA to 2e led to formation of a
negative LD signal in the absorption range of the ligand (Figure 6A). This negative LD signal of 2e
results from a parallel alignment of the transition dipole of the bound ligand and the ones of the
DNA bases, thus indicating the intercalative binding mode of the planar aromatic system of the
ligand.30 Further information about the relative orientation of the ligand in the binding site of DNA
is provided by the reduced linear dichroism, LDr, i.e. the wavelength dependent LD. In the case of
DNA-bound 2e, the LDr values in the absorption regions of the DNA bases and of the ligand are
negative and essentially independent of the absorption wavelength (Figure 6B), which confirms the
intercalation of the ligand into the DNA helix.30 Moreover, observation that the amplitude of the
LDr band of compound 2e has almost the same magnitude than the one of the DNA bases indicates
essentially coplanar alignment of the aromatic π system of the ligand to the DNA bases.
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Figure 6. Linear dichroism LD (A) and reduced linear dichroism LDr (B) spectra of ligand 2e in the
presence of ct DNA (cDNA = 50 μM, in base pairs) at LDR of 0 (- - -) and 0.04 (—) in BPE buffer (pH
7.0) with 2% v/v DMSO, T = 20 °C.
DNA-binding properties of photocyclization products E-4a,4b
Spectrophotometric titrations of the photoproducts E-4a and E-4b with ct DNA revealed non-
uniform changes in the absorption intensity with no isosbestic point (Figure 7A). In the first part of
the titration (ligand-DNA ratio (LDR): 110 – 7 for E-4a; 344 – 9 for E-4b), the absorption decreases
with a small red shift of the absorption maxima for E-4a or a pronounced blue shift for E-4b,
whereas at smaller ligand-DNA ratio (< 7 for E-4a; < 9 for E-4b) the absorption band increases
with a significant red shift. Such a behavior usually indicates the presence of at least two different
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binding modes. The complex changes observed during the photometric titrations of ct DNA to E-4a
and E-4b represent a superposition of changes arising from the different binding modes that cannot
be dissected. For this reason, calculation of the binding constant from the photometric data was not
possible.
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A special feature of the photometric titration of DNA to E-4b is the initial blue shift of the
absorption maximum at high LDR, which is rarely observed, for example on H-aggregate formation
of cyanine dyes along the DNA backbone.31 In the case of E-4b, however, the backbone
aggregation is rather unlikely because other than the cyanine dyes this ligand does not have the
molecular shape and flexibility such that its H-aggregates fit perfectly in the DNA groove.
Therefore, we assume that the blue shift is a result of a particular conformation of the DNA-bound
ligand. Because of its rather rod-like structure, E-4b may have significant twist about the alkene-
aryl bonds to provide a reasonable fit to the DNA binding sites. In this conformation, the styryl unit
is no longer well conjugated with the quinolizinium chromophore, so that a reduced donor-acceptor
interplay results a blue shift. Evidence for this assumption is provided by the observation that the
absorption maximum is close to the one of the DNA-bound benzo[c]quinolizinium ligands 2a and
2d that lack the styryl substituent.
For further investigation of the binding modes, CD- and flow-LD-spectroscopic analyses were
performed (Figure 7, C and D). In the case of ligand E-4a ICD bands were detected between 300
nm and 400 nm upon complexation with DNA (Figure 7, C1). Most notably, only a very weak ICD
bands developed in the long-wavelength absorption range of the ligand. This observation indicates
that the transition dipole moments of the DNA base pairs couple efficiently with the transition
dipole of the ligand that is assigned to the S0-S2 and/or S0-S3 transition (see discussion above). In
contrast, the coupling with the lower energy S0-S1 transition appears to be very weak, presumably
because of an unfavorable relative orientation of the respective transition dipoles towards each
other.30 In the flow-LD experiment, however, clear negative LD bands were recorded in the
absorption region of both transitions of the ligand E-4a (Figure 7, D1), thus indicating the
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intercalation of aromatic ligands into DNA (see discussion above).30 These observations clearly
indicate that one binding mode of ligand E-4a is intercalation, as unambiguously confirmed by the
negative LD bands of the ligand. In analogy to the ligands 2a and 2d (see above) the ligand E-4a
binds to DNA with the benzo[c]quinolizinium fragment inserted between the DNA base pairs,
whereas the dimethoxystyryl unit is pointing outside the DNA helix.
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In the case of ligand E-4b, the addition of DNA led to the development of a positive ICD and a
negative LD band only at ca. 450 nm (Figure 7, C2 and D2), that corresponds to the blue-shifted
absorption band formed at high ligand-DNA ratios, LDR > 9 (Figure 7, A2). Like in the case of E-
E-4a, these ICD and LD bands indicate the intercalation of the benzo[c]quinolizinium fragment.
But remarkably, the absorption band that was observed during photometric titration at smaller LDR
values (LDR < 9) is neither CD nor LD active. Such a lack of CD and LD spectroscopic response of
a DNA ligand is usually the result of unspecific aggregation along the DNA backbone, however,
this binding mode occurs at high LDR values and is usually negligible at low LDR. At the same
time, groove binding may be considered as alternative binding mode like for related styryl dyes,32
but groove-bound ligands usually give very strong ICD bands. Hence, along with the interpretation
of the unusual blue shift during photometric titration (see above), it may be proposed that at the
beginning of the titration, i.e. at high ligand-DNA ratio, the DNA is fully loaded with intercalated
molecules, each of which occupies several binding sites because a fairly large amout of the ligand
points outside the binding site and hinders the approach of another ligand in its close vicinity. With
decreasing LDR value the intercalating ligands are distributed less densely over the DNA molecule,
such that the ligand can also form aggregates the associate unselectively along the DNA backbone.
Apparently, the binding constants of both binding modes are in the same range so that they compete
at low LDR.
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Figure 7. A: Spectrophotometric titration of ct DNA to E-4a (A1, cE- = 50 μM, cDNA/cE- = 0–
4a
4a
13.3); E-4b (A2, cE- = 50 μM, cDNA/cE- = 0–23.8). B: Fluorimetric titration of ct DNA to E-4a
4b
4b
(B1, cE- = 25 μM, cDNA/cE- = 0–48.7, λex = 400 nm); E-4b (B2, cE- = 25 μM, cDNA cE- = 0–
4a
4a
4b
4b
48.0, λex = 400 nm). C: CD spectra of mixtures of ct DNA (cDNA = 0.1 μM, in base pairs) with
ligands E-4a (C1), E-4b (C2) at ligand-DNA ratio LDR = 0, 0.3, 0.6, 1.2. D: LD spectra of mixtures
of ct DNA (cDNA = 0.1 μM, in base pairs) with ligands E-4a (D1), E-4b (D2) at ligand-DNA ratio
LDR = 0, 0.3, 0.6, 1.2. In all cases: BPE buffer (pH 7.0) with 5% v/v DMSO (for the photometric
and fluorimetric titrations) or 7% v/v DMSO (for the CD and LD measurements), T = 20 °C. Blue
lines denote the initial absorption and fluorescence spectra of E-4a and E-4b; red lines denote the
corresponding spectra of DNA-bound E-4a and E-4b at saturation. Arrows indicate changes of the
bands upon addition of ct DNA.
Despite the structural similarity of compounds E-4a and E-4b, their emission properties in the
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presence of ct DNA differ significantly. Thus, upon increasing the concentration of DNA, the
fluorescence of E-4a was efficiently quenched with just residual increase at the end of the titration.
In addition, the emission maximum exhibited a pronounced red shift in the presence of DNA (Δλ =
44 nm) (Figure 7B, Table 1). By contrast, the fluorescence of E-4b lights up by a factor of 6.3 upon
addition of ct DNA with a negligible red shift of the emission maximum (Δλ = 3 nm) (Figure 7B,
Table 1). Most likely, this diverge behavior of the two ligands arises from a different contributions
of the two above-mentioned DNA binding modes in each case. By analogy to
benzo[c]quinolizinium intercalators 2a, 2d and 2e, whose fluorescence is completely quenched in
the presence of ct DNA (Figure 5B), we assume that intercalation of the benzo[c]quinolizinium
fragment of E-4a and E-4b between the DNA base pairs is also accompanied by fluorescence
quenching due to photoinduced PET processes, as described above.29 On the other hand, the
aggregation of the cationic styryl derivatives E-4b along the DNA backbone prevents the non-
radiative rotational relaxation and subsequently leads to the enhancement of the fluorescence
intensity, thus representing a special case of aggregation-induced enhancement of emission.33
Analysis of the fluorimetric data allowed to determine an average binding constant with ct DNA for
E-4b (Table 1) reflecting the combination of two binding modes.
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Conclusion
To sum up, we have demonstrated that ortho-styryl substituted N-heterocycles comprising one and
two nitrogen atoms generally undergo the regioselective C–N bond formation during
photocyclization resulting in formation of the family of (aza)benzo[c]quinolizinium derivatives.
The photocyclization of mono-styryl derivatives 1a, 1d and 1e occurs more efficiently in aqueous
solution than in organic solvents (acetonitrile) making the process environment-friendly. Bis-styryl
derivatives 3a and 3b – although designed for the two-fold cyclization – cyclize only one styryl
fragment, whereas the second styryl residue remains photochemically inert. DNA-binding studies
with ct DNA revealed that all obtained photoproducts have a high affinity towards nucleic acids.
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Interestingly, the photoproducts 2a, 2d, 2e of mono-styrylheterocycles are typical DNA-
intercalators, while the photoproducts E-4a and E-4b of bis-styrylheterocycles demonstrate a mixed
binding mode comprising intercalation and aggregation along the DNA backbone. Overall, the
studied phototransformation is the most simple synthetic approach, so far, to the
benzo[c]quinolizinium scaffold that may be applied in the development of new DNA-targeting
chemotherapeutics.
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Experimental section
1
All reagents and solvents were obtained from commercial sources and used as received. H NMR
13
spectra were recorded at 400 or 600 MHz, C NMR spectra were recorded at 101 or 151 MHz at
ambient temperature using 5 mm tubes. Chemical shifts were determined with accuracy of 0.01
1
13
ppm and 0.1 ppm for H and C spectra, respectively, and are given relative to the residual signal
of the solvent that was used as internal reference. Spin–spin coupling constants for the proton
spectra were determined with accuracy of 0.1 Hz. The 1H NMR signal assignments were performed
13
using COSY and NOESY 2D NMR techniques. The C NMR signal assignments were performed
by means of HSQC and HMBC 2D NMR techniques. Electrospray ionization (ESI) mass spectra
were detected in the mode of full mass scanning of positive ions on a tandem dynamic mass
spectrometer equipped with a mass analyzer with an octapole ionic trap. High-resolution mass
spectra were recorded on a time-of-flight instrument in a positive-ion mode using electrospray
ionization method. TLC was performed on silica gel on Al foils, eluent: EtOAc. Preparation and
handling of the solutions were carried out under red light. Photochemical reactions were carried out
with a high pressure Hg vapor lamp (120 W) and an immersed Hg photoreactor (125 W). Electronic
absorption spectra were measured on a fiber-optic spectrometer connected to a computer at 20±1°C.
Fluorescence spectra were measured on a spectrofluorimeter equipped with double-grating
monochromators and a Xe flash lamp at 20±1°C. Circular dichroism (CD) and linear dichroism
(LD) spectra were recorded on a CD spectrometer equipped with High Shear Couette Cell
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Accessory (for LD measurements). The LD samples were oriented in a rotating couette with a shear
gradient of 1200 s–1. The reduced linear dichroism, LDr, was calculated according to Eq. 1.
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LDr = LD / Aiso
(Eq. 1)
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9
where Aiso is the absorbance of an isotropic sample that is determined under the same conditions as
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the LD.
General Procedure for the Synthesis of mono-styryl derivatives (1a–1e) and bis-styryl
derivatives (3a, 3b)
A mixture of 3,4-dimethoxybenzaldehyde (for mono-styryl derivatives: 300 mg, 1.80 mmol; for bis-
styryl derivatives: 600 mg, 3.60 mmol), the corresponding methyl-substituted heterocycle [for 1a:
2-methylpyrazine (0.16 mL, 1.80 mmol); for 1b: 2-methylpyrimidine (0.17 mL, 1.80 mmol); for 1c:
4-methylpyrimidine (0.16 mL, 1.80 mmol); for 1d: 3-methylpyridazine (0.16 mL, 1.80 mmol); for
1e: 1-methylisoquinoline (0.24 mL, 1.80 mmol); for 3a: 2,5-dimethylpyrazine (197 L, 1.80
mmol); for 3b: 4,6-dimethylpyrimidine (199 L, 1.80 mmol)] and potassium tert-butoxide (for
mono-styryl derivatives: 202 mg, 1.80 mmol; for bis-styryl derivatives: 404 mg, 3.60 mmol) in abs.
DMF (for mono-styryl derivatives: 4 mL; for bis-styryl derivatives: 2.5 mL) was stirred at room
temperature for 2–4 h (mono-styryl derivatives) or 24 h (bis-styryl derivatives). The reaction
mixture was diluted with water (2 mL) and concentrated in vacuo. The obtained solid was dissolved
in water (30 mL) and extracted with dichloromethane (5 х 20 mL). The organic layers were
combined and the solvent was removed.
(E)-2-(3,4-dimethoxystyryl)pyrazine (1a)
Recrystallized from MeOH; yellow solid, yield 51% (0.91 mmol, 220 mg), mp 103–105 °С (lit. mp
107–108 °С)34. 1H NMR (DMSO-d6, 400 MHz) δ: 3.79 (s, 3Н, ОСН3), 3.84 (s, 3Н, ОСН3), 6.99 (d,
1Н, Н-5', J = 8.3 Hz), 7.20 (br.d, 1Н, Н-6', J = 8.3), 7.28 (d, 1Н, Н-a, Jtrans = 16.1 Hz), 7.34 (br. s,
1Н, Н-2'), 7.72 (d, 1Н, Н-b, Jtrans = 16.1 Hz), 8.45 (d, 1Н, Н-6, J = 2.4 Hz), 8.59 (br. s, 1Н, Н-5),
13
8.75 (br. s, 1Н, Н-3). C NMR (DMSO-d6, 100 MHz) δ: 55.5 (2C, OCH3), 109.6, 111.7, 121.4,
122.2, 128.8, 134.4, 142.6, 143.5, 144.4, 149.0, 149.8, 151.1. Anal. Calcd for C14H14N2O2: C,
69.41; H, 5.82; N, 11.56; found: C, 69.20; H, 5.81; N, 11.49. ESI-MS 1a in MeCN, m/z: calcd.
242.27; found 243.10 [1a+H]+.
(E)-2-(3,4-dimethoxystyryl)pyrimidine (1b)
Further purification was not required; white solid, yield 53% (0.95 mmol, 230 mg), mp 110–112
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°С. 1H NMR (CD3CN, 600 MHz) δ: 3.83 (s, 3Н, ОСН3), 3.87 (s, 3Н, ОСН3), 6.96 (d, 1Н, Н-5', J =
8.3 Hz), 7.15 (d, 1Н, Н-а, Jtrans = 15.9 Hz), 7.16 (t, 1Н, Н-5, J = 4.8 Hz, 9.6 Hz), 7.22 (d, 1Н, Н-6',
J = 8.6 Hz), 7.30 (s, 1Н, Н-2'), 7.91 (d, 1H, H-b, Jtrans = 15.9 Hz), 8.70 (d, 2Н, Н-4, Н-6, J = 4.8
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8
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Hz). C NMR (CD3CN, 151 MHz) δ: 56.6 (m-OCH3), 56. 7 (p-OCH3), 111.1 (C-2'), 112.8 (C-5'),
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119.8 (C-5), 122.9 (C-6'), 126.8 (C-a), 130.2 (C-1'), 138.6 (C-b), 150.7 (C-3'), 151.7 (C-4'), 158.4
(2C, C-4, C-6), 166.1 (C-2). Anal. Calcd for C14H14N2O2: C, 69.41; H, 5.82; N, 11.56; found: C,
69.48; H, 5.89; N, 11.61. ESI-MS 1b in MeCN, m/z: calcd. 242.27; found 243.60 [1b+H]+. HRMS
(ESI-TOF) m/z: [1b–H]+ Calcd for C14H13N2O2 241.0972; Found 241.0973.
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(E)-4-(3,4-dimethoxystyryl)pyrimidine (1c)
1
Recrystallized from MeOH; yellow solid, yield 52% (0.94 mmol, 227 mg), mp 108–110 °С. Н
NMR (CD3CN, 600 MHz) δ: 3.86 (s, 3Н, ОСН3), 3.90 (s, 3Н, ОСН3), 6.99 (d, 1Н, Н-5', J = 8.4),
7.11 (d, 1Н, Н-a, Jtrans = 16.0 Hz), 7.24 (d, 1Н, Н-6', J = 8.4 Hz), 7.31 (br. s., 1Н, Н-2'), 7.42 (d, 1Н,
Н-3, J = 5.3 Hz), 7.88 (d, 1Н, Н-b, Jtrans = 16.0 Hz), 8.66 (d, 1Н, Н-6, J = 5.1 Hz), 9.08 (s, 1Н, Н-
4). 13C NMR (CD3CN, 151 MHz) δ: 56.4 (2C, OCH3), 110.9 (С-2'), 112.6 (C-5'), 119.6 (C-5), 122.9
(C-6'), 124.8 (C-a), 129.7 (C-1'), 137.8 (C-b), 150.5 (C-3'), 151.7 (C-4'), 158.5 (C-6), 159.7 (C-2),
163.5 (C-4). Anal. Calcd for C14H14N2O2: C, 69.41; H, 5.82; N, 11.56; found: C, 69.50; H, 5.84; N,
11.56. ESI-MS 1c in MeCN, m/z: calcd. 242.27; found 243.50 [1c+H]+. HRMS (ESI-TOF) m/z:
[1c–H]+ Calcd for C14H13N2O2 241.0972; Found 241.0978.
(E)-3-(3,4-dimethoxystyryl)pyridazine (1d)
The residue was purified by column chromatography (SiO2; ethylacetate; Rf = 0.80); pale yellow
1
solid, yield 48% (0.86 mmol, 208 mg), mp 83–85 °С. H NMR (DMSO-d6, 600 MHz) δ: 3.80 (s,
3Н, ОСН3), 3.85 (s, 3Н, ОСН3), 7.01 (d, 1H, H-5', J = 8.4 Hz), 7.22 (dd, 1H, H-6', J = 8.4 Hz; 2.0
Hz), 7.35 (d, 1H, H-b, Jtrans = 16.1 Hz), 7.36 (d, 1H, H-2', J = 2.0 Hz), 7.65 (dd, 1H, H-5, J = 8.4
Hz; 4.8 Hz), 7.73 (d, 1H, H-a, Jtrans = 16.5 Hz), 7.90 (dd, 1H, H-4, J = 8.8 Hz; 1.6 Hz), 9.06 (dd,
1H, H-6, J = 4.8 Hz; 1.2 Hz). 13C NMR (DMSO-d6, 151 MHz) δ: 55.50 (3'-OCH3), 55.52 (4'-
OCH3), 109.8 (C-2'), 111.8 (C-5'), 121.2 (C-6'), 123.1 (C-a), 123.9 (C-4), 126.8 (C-5), 128.8 (C-1'),
134.5 (C-b), 149.0 (C-3'), 149.6 (C-6), 149.8 (C-4'), 158.1 (C-3). Anal. Calcd for C14H14N2O2: C,
69.41; H, 5.82; N, 11.56; found: C, 69.56; H, 5.89; N, 11.47. HRMS (ESI-TOF) m/z: [1d+H]+
Calcd for C14H15N2O2 243.1128; Found 243.1132.
(E)-1-(3,4-dimethoxystyryl)isoquinoline (1e)
The residue was purified by column chromatography (SiO2; benzene–ethylacetate going from 1:0 to
80:20; Rf = 0.80); yellow solid, yield 35% (0.63 mmol, 184 mg), mp 134–137 °С (lit. mp 136–137
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°С)34. 1Н NMR (acetone-d6, 400 MHz) δ: 3.87 (s, 3Н, ОСН3), 3.93 (s, 3Н, ОСН3), 7.01 (d, 1Н, Н-
5', J = 8.1 Hz), 7.33 (d, 1Н, Н-6', J = 8.5 Hz), 7.53 (br. s., 1Н, Н-2'), 7.65-7.69 (m, 2Н, Н-4, H-7),
7.75 (t, 1Н, Н-6, J = 7.2 Hz), 7.94 (d, 1Н, Н-5, J = 8.2 Hz), 8.04 (d, 1Н, Н-b, Jtrans = 15.4 Hz), 8.15
(d, 1Н, Н-a, Jtrans = 15.4 Hz), 8.52 (d, 1H, H-3, J = 5.5 Hz), 8.61 (d, 1H, H-8, J = 8.2 Hz). 13C NMR
(acetone-d6, 101 MHz) δ: 56.2 (p-OCH3), 56.3 (m-OCH3), 111.3 (C-2'), 112.8 (C-5'), 120.2 (C-4),
121.4 (C-a), 122.5 (C-6'), 125.6 (C-8), 127.5 (C-8a), 128.1 (C-7), 128.2 (C-5), 130.8 (C-6), 131.1
(C-1'), 136.6 (C-b), 137.8 (C-4a), 143.5 (C-3), 150.8 (C-3'), 151.4 (C-4'), 155.5 (C-1). Anal. Calcd
for C19H17NO2: C, 78.33; H, 5.88; N, 4.81; found: C, 78.28; H, 5.84; N, 4.75. ESI-MS 1e in MeCN,
m/z: calcd. 291.34; found 292.40 [1e+H]+.
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(E,E)-2,5-bis(3,4-dimethoxystyryl)pyrazine (3a)
Recrystallized from methanol; orange solid, yield 20% (0.36 mmol, 142 mg), mp 222–224 °С (lit.
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mp 214 °С and 229 °С for two polymorphic forms)35. Н NMR (DMSO-d6, 600 MHz) δ: 3.79 (s,
6Н, ОСН3), 3.84 (s, 6Н, ОСН3), 7.00 (d, 2Н, Н-5', J = 8.3 Hz), 7.21 (d, 2Н, Н-6', J = 8.5 Hz), 7.31
(d, 2H, H-b, Jtrans = 16.1 Hz), 7.35 (s, 2H, H-2'), 7.70 (d, 2Н, Н-а, Jtrans = 16.0 Hz), 8.68 (s, 2Н, Н-2,
Н-5). 13C NMR (DMSO-d6, 151 MHz) δ: 55.5 (OCH3), 109.5 (C-5'), 111.7 (C-2'), 121.3 (C-6'),
122.3 (C-a), 129.1 (C-1'), 133.4 (C-b), 143.1 (C-3), 148.7 (C-3'), 149.0 (C-4'), 149.7 (C-2). Anal.
Calcd for C24H24N2O4: C, 71.27; H, 5.98; N, 6.93; found: C, 71.30; H, 6.01; N, 6.98. ESI-MS 3a in
MeCN, m/z: calcd. 404.46; found 405.60 [3a+H]+.
(E,E)-4,6-bis(3,4-dimethoxystyryl)pyrimidine (3b)
Purified by column chromatography (SiO2, benzene–ethylacetate 10:1, Rf = 0.64) and then
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recrystallized from methanol; yellow solid, yield 23% (0.41 mmol, 170 mg), mp 128–131 °С. Н
NMR (acetone-d6, 400 MHz) δ: 3.86 (s, 6Н, ОСН3), 3.90 (s, 6Н, ОСН3), 7.01 (d, 2H, H-5', J = 8.3
Hz), 7.12 (d, 2Н, H-a, Jtrans = 15.9 Hz), 7.23 (d, 2Н, Н-6', J = 8.2 Hz), 7.36 (s, 2H, H-2'), 7.48 (s,
1H, H-5), 7.92 (d, 2Н, Н-b, Jtrans = 16.1 Hz), 8.97 (s, 1Н, Н-2). 13C NMR (acetone-d6, 101 MHz) δ:
56.2 (-OCH3), 111.0 (C-2'), 112.6 (C-5'), 116.7 (C-5), 122.7 (C-6'), 124.9 (C-a), 129.9 (C-3'), 137.5
(C-b), 150.7 (C-1'), 151.8 (C-4'), 159.4 (C-2), 164.0 (C-4). Anal. Calcd for C24H24N2O4: C, 71.27;
H, 5.98; N, 6.93; found: C, 71.15; H, 5.95; N, 6.88. ESI-MS 3b in MeCN, m/z: calcd. 404.46; found
405.50 [3b+H]+. HRMS (ESI-TOF) m/z: [3b–H]+ Calcd for C24H23N2O4 403.1652; Found
403.1645.
General Procedure for the synthesis of the photocyclization products (2a, 2d, 2e, E-4a, E-4b)
A solution of the substrate (30.0 mg; 1a: 0.12 mmol, 1d: 0.12 mmol, 1e: 0.10 mmol, 3a: 0.07 mmol,
3b: 0.07 mmol) in acetonitrile (1 mM) was irradiated in an immersion well with a Hg photoreactor
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(125 W), and the reaction was monitored photometrically. When a maximum conversion was
reached the solvent was removed in vacuum, the residue was washed with hexane and recrystallized
from MeOH with addition of HClO4 to give the photocyclization products 2a, 2d, 2e, E-4a, E-4b as
perchlorate salts.
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8,9-dimethoxypyrazino[1,2-a]quinolin-11-ium perchlorate (2a)
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Brownish solid, yield 39% (0.05 mmol, 17.0 mg), mp 280–282 °С (dest). H NMR (CD3CN, 600
MHz) δ: 4.11 (s, 3H, 3'-OCH3), 4.22 (s, 3H, 4'-OCH3), 7.79 (s, 1H, H-2'), 8.09 (s, 1H, H-5'), 8.34
(d, 1H, H-a, J = 8.7 Hz), 8.83 (d, 1H, H-b, J = 8.7 Hz), 9.00 (d, 1H, H-5, J = 4.8 Hz), 9.57 (d, 1H,
H-6, J = 4.8 Hz), 9.79 (s, 1H, H-3). 13C NMR (CD3CN, 151 MHz) δ: 57.8 (8-OCH3), 58.4 (9-
OCH3), 99.2 (C-10), 109.7 (C-7), 120.0 (C-5), 123.2 (C-1), 126.9 (C-6a), 130.8 (C-10a), 135.2 (C-
4a), 140.3 (C-6), 141.3 (C-2), 154.7 (C-4), 154.8 (C-8), 157.5 (C-9). Anal. Calcd for C14H13ClN2O6:
C, 49.35; H, 3.85; N, 8.22; found: C, 49.31; H, 3.95; N, 8.30. HRMS (ESI-TOF) m/z: [2a]+ Calcd
for C14H13N2O2 241.0972; Found 241.0972.
8,9-dimethoxypyridazino[1,6-a]quinolin-11-ium perchlorate (2d)
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Brown solid, yield 57% (0.07 mmol, 23.9 mg), mp 183–186 °С (dest). H NMR (DMSO-d6, 600
MHz) δ: 4.08 (s, 3H, 8-OCH3), 4.15 (s, 3H, 9-OCH3), 7.96 (s, 1H, H-7), 8.30 (dd, 1H, H-3, J = 8.8
Hz; 4.8 Hz), 8.39 (d, 1H, H-5, J = 8.8 Hz), 8.55 (s, 1H, H-10), 8.95 (d, 1H, H-6, J = 8.8 Hz), 9.05
(d, 1H, H-4, J = 8.8 Hz), 9.62 (d, 1H, H-2, J = 4.4 Hz). 13C NMR (DMSO-d6, 151 MHz) δ: 56.6 (8-
OCH3), 56.8 (9-OCH3), 98.5 (C-10), 108.0 (C-7), 120.5 (C-5), 124.5 (C-6a), 127.3 (C-3), 133.9 (C-
10a), 135.8 (C-4), 138.7 (C-6), 140.5 (C-4a), 150.9 (C-2), 152.3 (C-8), 155.3 (C-9). Anal. Calcd for
C14H13ClN2O6: C, 49.35; H, 3.85; N, 8.22; found: C, 49.59; H, 3.91; N, 8.38. HRMS (ESI-TOF)
m/z: [2d]+ Calcd for C14H13N2O2 241.0972; Found 241.0968.
2,3-dimethoxyisoquinolino[2,1-a]quinolinium perchlorate (2e)
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Orange solid, yield 50% (0.05 mmol, 19.5 mg), mp 327–329 °С (dest). H NMR (CD3CN, 400
MHz) δ: 4.11 (s, 3H, 3-OCH3), 4.25 (s, 3H, 2-OCH3), 7.75 (s, 1H, H-4), 8.08 (s, 1H, H-1), 8.10 (t,
1H, J = 7.7 Hz, H-8), 8.16 (t, 1H, J = 7.0 Hz, H-9), 8.27 (d, 1H, J = 8.2 Hz, H-10), 8.31 (d, 1H, J =
7.7 Hz, H-11), 8.80 (d, 1H, J = 9.2 Hz, H-5), 9.01 (d, 1H, J = 8.2 Hz, H-7 ), 9.02 (d, 1H, J = 9.2 Hz,
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H-6), 9.52 (d, 1H, J = 7.7 Hz, H-12). C NMR (CD3CN, 101 MHz) δ: 57.5 (3-OCH3), 58.2 (2-
OCH3), 100.0 (C-1), 109.7 (C-4), 117.2 (C-6), 123.7 (C-11), 124.6 (C-4a), 127.1 (C-7, C-7a), 127.3
(C-12), 129.1 (C-10), 132.3 (C-8), 133.1 (C-10a), 133.3 (C-1a), 135.4 (C-9), 139.8 (C-5), 143.7 (C-
6a), 153.0 (C-3), 157.2 (C-2). Anal. Calcd for C19H16ClNO6: C, 58.55; H, 4.14; N, 3.59; found: C,
58.48; H, 4.09; N, 3.57. ESI-MS 2e in MeCN, m/z: calcd. 290.34; found 290.10 [2e]+. HRMS (ESI-
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(E)-2-(3,4-dimethoxystyryl)-8,9-dimethoxypyrazino[1,2-a]quinolin-11-ium perchlorate (E-4a)
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Red solid, yield 25% (0.02 mmol, 10.1 mg), mp 289–292 °С (dest). H NMR (CD3CN, 600 MHz)
δ: 3.86 (s, 3H, 4'-OCH3), 3.90 (s, 3H, 3'-OCH3), 4.10 (s, 3H, 8-OCH3), 4.26 (s, 3H, 9-OCH3), 7.00
(d, 1H, H-5', J = 8.2 Hz), 7.27 (d, 1H, H-6', J = 8.2 Hz), 7.29 (s, 1H, H-2' Hz), 7.48 (d, 1H. H-b,
Jtrans = 15.8 Hz), 7.72 (s, 1H, H-7), 8.02 (d, 1H, H-a, Jtrans = 15.7 Hz), 8.08 (s, 1H, H-10), 8.26 (d,
1H, H-5, J = 8.8 Hz), 8.65 (d, 1H, H-6, J = 8.7 Hz), 9.38 (s, 1H, H-1), 9.67 (s, 1H, H-4). 13C NMR
(CD3CN, 151 MHz) δ: 56.7 (3'-OCH3), 56.8 (4'-OCH3), 58.0 (8-OCH3), 58.7 (9-OCH3), 99.4 (C-
10), 110.0 (C-7), 111.2 (C-2'), 113.0 (C-5'), 120.5 (C-1), 120.6 (C-b), 121.1 (C-a), 121.4 (C-5),
123.3 (C-6'), 127.3 (C-6a), 129.8 (C-1'), 130.9 (C-10a) 133.5 (C-4a), 139.0 (C-6), 150.2 (C-2),
150.8 (C-3'), 152.4 (C-4'), 155.0 (C-4), 155.9 (C-8), 157.5 (C-9). Anal. Calcd for C24H23ClN2O8: C,
57.32; H, 4.61; N, 5.57; found: C, 57.38; H, 4.59; N, 5.59. HRMS (ESI-TOF) m/z: [E-4a]+ Calcd
for C24H23N2O4 403.1652; Found 403.1656.
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(E)-2-(3,4-dimethoxystyryl)-8,9-dimethoxypyrimido[1,6-a]quinolin-11-ium perchlorate (E-4b)
Red solid, yield 51% (0.04 mmol, 18.3 mg), mp 340–345 °С (dest). 1H NMR (DMSO-d6, 600 MHz)
δ: 3.85 (s, 3H, 3'-OCH3), 3.89 (s, 3H, 4'-OCH3), 4.03 (s, 3H, 8-OCH3), 4.17 (s, 3H, 9-OCH3), 7.09
(d, 1H, H-5', J = 8.2 Hz), 7.40 (d, 1H, H-6', J = 8.0 Hz), 7.49 (s, 1H, H-2'), 7.56 (d, 1H. H-a, Jtrans
=
15.5 Hz), 7.88 (s, 1H, H-7), 8.10 (d, 1H, H-5, J = 8.2 Hz), 8.13 (d, 1H, H-b, Jtrans = 15.5 Hz), 8.34
(s, 1H, H-4), 8.54 (s, 1H, H-10), 8.70 (d, 1H, H-6, J = 8.2 Hz), 10.84 (s, 1H, H-1). 13C NMR
(DMSO-d6, 151 MHz) δ: 55.7 (3'-OCH3, 4'-OCH3), 56.4 (8-OCH3), 57.4 (9-OCH3), 99.2 (C-10),
109.4 (C-7), 110.4 (C-2'), 111.8 (C-5'), 115.9 (C-4), 119.6 (C-5), 121.7 (C-a), 122.4 (C-6a), 123.6
(C-6'), 127.9 (C-1’), 129.3 (C-6), 139.9 (C-10a) 141.2 (C-b), 144.4 (C-4a, C-1), 149.2 (C-3’), 151.0
(C-8), 151.4 (C-4'), 154.6 (C-9), 156.3 (C-3). Anal. Calcd for C24H23ClN2O8: C, 57.32; H, 4.61; N,
5.57; found: C, 57.40; H, 4.64; N, 5.60. HRMS (ESI-TOF) m/z: [E-4b]+ Calcd for C24H23N2O4
403.1652; Found 403.1648.
Photochemical studies
The solutions of 1a–1e and 3a, 3b (c = 20 μM) in acetonitrile or water were irradiated either with
filtered light (λ > 295 nm) or with full light of a high pressure mercury vapor lamp (120 W).
Individual lines of the lamp emission spectrum (λ = 365, 405 nm) were isolated with glass filters.
All photoreactions were carried out in air-saturated solutions under stirring. The analysis of the
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Supporting Information
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1H and 13C NMR spectra, HRMS data for all new compounds, optical spectroscopy and
photochemical studies data. This material is available free of charge via the Internet at
http://pubs.acs.org.
Author information
Corresponding authors
*E-mail: berdnikova@chemie-bio.uni-siegen.de; daria@ineos.ac.ru
Notes
The authors declare no competing financial interest.
Acknowledgements
Generous support by the Russian Science Foundation (project 16-13-10226) and the Deutsche
Forschungsgemeinschaft (project IH24/13-1) is gratefully acknowledged. T. A. thanks the Deutsche
Akademische Austauschdienst (project 57130097). We thank Ms. Jennifer Hermann for technical
assistance.
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