Catalyst-free assembly of giant tris(heteroaryl)methanes: Synthesis of novel pharmacophoric triads and model sterically crowded tris(heteroaryl/aryl)methyl cation salts

Article abstract of DOI:10.3762/bjoc.15.60

A series of giant tris(heteroaryl)methanes are easily assembled by one-pot three-component synthesis by simple reflux in ethanol without catalyst or additives. Diversely substituted indoles (Ar¹) react with quinoline aldehydes, quinolone aldehydes, chromone aldehydes, and fluorene aldehydes (Ar²CHO) and coumarins (Ar³) in 1:1:1 ratio to form the corresponding tris(heteroaryl)methanes (Ar¹Ar²Ar³)CH along with (Ar¹Ar¹Ar²)CH triads. A series of new 2:1 triads were also synthesized by coupling substituted indoles with Ar²CHO. The coupling reactions could also be carried out in water (at circa 80 °C) but with chemoselectivity favoring (Ar¹Ar¹Ar²)CH(Ar¹Ar²Ar³)CH. The molecular structure of a representative (Ar¹Ar²Ar³)CH triad was confirmed by X-ray analysis. Model tris(heteroaryl/aryl)methylium salts were generated by reaction with DDQ/HPF₆ and studied by NMR and by DFT and GIAO-DFT.

Full text of DOI:10.3762/bjoc.15.60

Catalyst-free assembly of giant tris(heteroaryl)methanes:
synthesis of novel pharmacophoric triads and model
sterically crowded tris(heteroaryl/aryl)methyl cation salts
Rodrigo Abonia1, Luisa F. Gutiérrez1,2, Braulio Insuasty1, Jairo Quiroga1,
Kenneth K. Laali*2, Chunqing Zhao2, Gabriela L. Borosky3, Samantha M. Horwitz4
and Scott D. Bunge4
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2019, 15, 642–654.
1
Research Group of Heterocyclic Compounds (GICH), Department of
Chemistry, Universidad del Valle, A. A. 25360, Cali, Colombia,
Department of Chemistry, University of North Florida, 1 UNF Drive,
doi:10.3762/bjoc.15.60
2
Received: 06 December 2018
Accepted: 26 February 2019
Published: 12 March 2019
Jacksonville, FL 32224, USA, 3INFIQC, CONICET and Departamento
de Química Teórica y Computacional, Facultad de Ciencias
Químicas, Universidad Nacional de Córdoba, Ciudad Universitaria,
Córdoba 5000, Argentina and 4Department of Chemistry and
Biochemistry, Kent State University, Kent, OH 44242, USA
This article is part of the thematic issue "Multicomponent reactions III".
Guest Editor: T. J. J. Müller
Email:
Kenneth K. Laali* - Kenneth.Laali@UNF.edu
© 2019 Abonia et al.; licensee Beilstein-Institut.
License and terms: see end of document.
*
Corresponding author
Keywords:
model heteroarylmethylium salts; multicomponent; one-pot
catalyst-free assembly; pharmacophoric triads; three-component
synthesis; tris(heteroaryl)methanes; Yonemitsu-type reaction
Abstract
A series of giant tris(heteroaryl)methanes are easily assembled by one-pot three-component synthesis by simple reflux in ethanol
without catalyst or additives. Diversely substituted indoles (Ar1) react with quinoline aldehydes, quinolone aldehydes, chromone
aldehydes, and fluorene aldehydes (Ar2CHO) and coumarins (Ar3) in 1:1:1 ratio to form the corresponding tris(heteroaryl)methanes
(
Ar1Ar2Ar3)CH along with (Ar1Ar1Ar2)CH triads. A series of new 2:1 triads were also synthesized by coupling substituted indoles
with Ar2CHO. The coupling reactions could also be carried out in water (at circa 80 °C) but with chemoselectivity favoring
Ar1Ar1Ar2)CH over (Ar1Ar2Ar3)CH. The molecular structure of a representative (Ar1Ar2Ar3)CH triad was confirmed by X-ray
(
analysis. Model tris(heteroaryl/aryl)methylium salts were generated by reaction with DDQ/HPF6 and studied by NMR and by DFT
and GIAO-DFT.
Introduction
During the last few decades multicomponent reactions (MCRs) logical and practical interest. This approach offers several
have gained importance as a suitable strategy for the synthesis advantages including simplicity, high reaction rates, and high
of diverse synthetic and naturally occurring compounds of bio- bond-forming efficiency [1-5]. Furthermore, it is highly desir-
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Beilstein J. Org. Chem. 2019, 15, 642–654.
able to perform these reactions in environmentally friendly sol- develop more specific drugs for the treatment of persistent and
vents such as water, ethanol, and PEG [6,7].
challenging pathologies [27,28] (Scheme 1).
Motifs bearing triarylmethane (Ar3CH) [8-10] and their hetero- The indole, coumarin, quinoline, chromone and fluorene
cyclic variants (Het-Ar)3CH [8-12], constitute an integral part moieties are a set of “privileged structural motifs” that are
of a number of bioactive compounds [13-16]. Due to their valu- present in both synthetic and naturally occurring compounds of
able properties, they are also well exploited by the chemical practical and biological interest [29-36]. Consequently, there
industry as dyes and photochromic agents [17,18], protective have been many attempts to produce hybrid structures with
groups in organic synthesis [19] and as building blocks for interesting properties by combining two such pharmacophores
dendrimers [20] and nonlinear optical (NLO) properties [21] in one molecule, using both catalytic and non-catalytic reac-
(
Scheme 1). Numerous methods for the construction of triaryl- tions [37-48].
methane frameworks have been developed, with the majority of
them bearing simple diaryl or triaryl moieties in their structures However, a remaining challenge is to discover methods to
[
22], and many are performed in multistep processes or require construct asymmetric triads consisting of three different
harsh reaction conditions [1-22]. Although, “Yonemitsu-type” pharmacophores (i.e., heterodimeric entities) via a simple
three-component reactions have been employed for the synthe- synthetic step. According to the literature, most attempts
sis of indole-based triarylmethanes [23-26] (Scheme 2), there in this direction have resulted in isolation of symmetric
still exists a need for the development of new approaches for and asymmetric bis(indolyl)methane derivatives as the main
easy access to libraries of triarylmethanes of higher complexity components [39-41,49-52] (Scheme 1). Some exceptions
by employing simpler, more efficient, catalytic methods that are to this tendency have been reported by Appendino et al.
also environmentally friendly.
[52] and by Mousavizadeh et al. [53] through the three-compo-
nent reactions of indole and coumarin, but in all cases, ordinary
Molecular hybridization has emerged as an interesting strategy aliphatic and aromatic aldehydes as the third partner, mediated
for the synthesis of bioactive molecules with improved proper- by a catalyst or by a biphasic system as solvent, respectively,
ties by combining two or more pharmacophore fragments in a were used. The lack of structural diversity in the indole and
new structure. This concept has recently received attention by coumarin partners also characterizes these approaches,
the pharmaceutical industry because it provides new options to Scheme 2.
Scheme 1: Representative examples of tris(hetero/aryl)methanes, molecular hybrids and bis(indolyl)methanes with useful properties.
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Scheme 2: Previous synthetic approaches for the synthesis of triarylmethane analogues in comparison to the present study.
Continuing our current program on the synthesis of quinoline- Results and Discussion
based heterocyclic compounds of biological interest [54-57], we At the onset a series of non-commercial N-alkylindoles 1{4–10}
describe here a Yonemitsu-based direct and reproducible three- and quinoline-/quinolone aldehydes 6{1-7} were prepared
component synthesis of ternary heteroarylmethane-inspired (Scheme 3 and Scheme 4). The N-methyl-, N-butyl- and
hybrids by coupling diversely substituted indoles (Ar1) with N-benzylindoles 1{4–10} were synthesized in 80–98% yield by
quinoline aldehydes, quinolone aldehydes, chromone aldehydes, N-alkylation of commercially available N–H indoles 1{1–3}
and fluorene aldehydes (Ar2CHO) and coumarins (Ar3) in 1:1:1 ({1} R = H; {2} R = F and {3} R = OMe), by adopting a
ratio by simple reflux in ethanol solvent to form the correspond- procedure similar to that described by Kong et al. [58]
ing highly crowded tris(heteroaryl)methanes (Ar1Ar2Ar3)CH (Scheme 3).
(
Scheme 2). Formation of (Ar1Ar1Ar2)CH triads is a competing
process, whose relative proportion varies depending on the The quinolone aldehydes 5 were synthesized via 2-chloroquino-
choice of the substituents. The efficacy to perform these line-3-carbaldehydes 4 mediated by a Meth-Cohn type method-
remarkable reactions in water as solvent, and to generate highly ology through the Vilsmeier–Haack (DMF + POCl3) reagent
crowded triarylmethylium salts by hydride abstraction from [59,60]. A subsequent sequence of hydrolysis and N/O-alkyl-
(
Ar1Ar1Ar2)CH are also demonstrated.
ation processes, respectively, afforded the starting quinoline-/
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Beilstein J. Org. Chem. 2019, 15, 642–654.
quinoline aldehyde 6{1} (1.0 equiv) and coumarin 7{1}
(
1.0 equiv) in ethanol as solvent with no catalyst. The mixture
was subjected to stirring at ambient temperature, and the reac-
tion progress was monitored by TLC. After 24 h, the starting
materials 1{1} and 6{1} were almost totally consumed, but
several spots were observed (including unreacted 7{1}), with
two of them as main components. A white solid fell out of solu-
tion, which was collected by filtration and washed with cold
ethanol. NMR and HRMS analysis showed that it corresponded
to the bisindole derivative 8{1,1,1}. The remaining crude reac-
tion mixture was purified by column chromatography, and led
to isolation of a second major component corresponding to the
desired three-component product 9{1,1,1}. The relative weight
Scheme 3: Synthesis of the starting N-alkylindoles 1{4–10}.
quinolone aldehydes 6{1–7} in 70–85% yield as described pre- ratios of the two isolated products 8{1,1,1} and 9{1,1,1} were
viously [54] (Scheme 4).
circa 1:1 (Scheme 6).
Additionally, a chemset of hydroxycoumarins 7{1–4} These initial findings encouraged us to perform an in-depth
Scheme 5) was chosen as the second source of nucleophilic study aimed at optimizing chemoselectivity. As a model
partners for elaboration in our MCR experiments. reaction, an equimolar three-component mixture of precursors
{1}, 6{2} and 7{1} was subjected to various catalyzed and
(
1
With these building blocks at hand, an initial three-component uncatalyzed conditions and the results are summarized in
assay was performed starting with indole 1{1} (1.0 equiv), Table 1.
Scheme 4: General procedure for the synthesis of the starting quinoline-/quinolone aldehydes 6{1–7}.
Scheme 5: Chemset of coumarins 7{1–4} for elaboration in the MCR experiments.
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Beilstein J. Org. Chem. 2019, 15, 642–654.
Scheme 6: Exploratory reaction leading to isolation of products 8{1,1,1} and 9{1,1,1}.
Table 1: Optimization of the reaction conditions for the three-component synthesis of triads 8{1,1,2} and 9{1,2,1}.
entrya
solvent
2 mL)
catalyst
(mol %)
temp.
(°C)
time
(h)
bisindole triad 8{1,1,2}
tris-triad 9{1,2,1}
(
(% w/w)
(% w/w)
1
2
3
4
5
6
7
8
9
EtOH
EtOH
ACN
ACN
ACN
ACN
ACN
ACN
ACN
EtOHb
H2O
–
–
rt
24
3
≈50
≈50
100
100
100
100
100
100
≈50
≈50
≈67
≈50
≈50
–
reflux
Yb(OTf)3 (5)
Sc(OTf)3 (5)
Al(OTf)3 (5)
Bi(OTf)3 (5)
I2 (5)
rt
6
rt
3
–
rt
3
–
rt
3
–
rt
rt
1
–
BF3·OEt (5)
–
2
–
rt
48
8
≈50
≈50
≈33
10
1
AcOH (0.5 mL)
–
rt
1
reflux
3
aAll reactions were performed starting with compound 1{1} (10 mg), 6{2} (20 mg) and 7{1} (13 mg) corresponding to a 1:1:1 mmolar ratio. b1.5 mL of
EtOH was used.
Further studies showed that the Lewis acid-catalyzed reactions entry 1). Finally, performing the reaction in hot water instead of
(
Table 1, entries 3–8) greatly favored the formation of bisin- EtOH resulted in a 2:1 mixture of 8 and 9.
dole triad 8{1,1,2}, while EtOH at room temperature produced
an optimal (circa 1:1 w/w) mixture of 8{1,1,2} and 9{1,2,1} Using the outcomes in Table 1 as a guide, an adaptation of entry
(
Table 1, entry 1), and reflux accelerated the process without 3 was chosen to obtain a library of diversely substituted bisin-
affecting the w/w ratio (Table 1, entry 2). The reaction time was dole triads 8. Since coumarin 7 remained unreacted in this ap-
notably shorter in EtOH at rt in the presence of AcOH as cata- proach the examples described in Figure 1 were performed by
lyst (Table 1, entry 10), while longer reaction times were noted employing a 2:1 ratio of precursors 1 and 6, respectively, in the
when MeCN was used as solvent at rt (compare entry 9 and absence of coumarin 7.
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Figure 1: Pseudo-three-component synthesis of bisindole triads 8 employing quinoline-/quinolone-CHO 6{1–6}, chromone-CHO 6{8–9} and fluorene-
CHO 6{10} as coupling partners. Although entries 4 and 7 (Table 1) were satisfactory, reactions of Figure 1 were performed by following an adapta-
tion of entry 3 (using Yb(OTf)3 with a 2:1 ratio of 1 and 6, respectively) due to lower catalyst cost (in comparison with Sc(OTf)3) and/or easier work-up
(in comparison with I2) (see experimental section). aThis product was obtained as an inseparable mixture along compound 9{9,6,2} from the ap-
proach described in entry 2 of Table 1 (see also Supporting Information File 1).
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Beilstein J. Org. Chem. 2019, 15, 642–654.
For a broader scope of this approach, bisindole triads 8{4,4,8}, ful [61], presumably due to extreme steric crowding, the reac-
8
{4,4,9}, 8{10,10,9} and 8{1,1,10} were also synthesized in tion with DDQ/HPF6 (Scheme 8) [62-65] was successful and
good yields by replacing the corresponding quinoline-/ the methylium-PF6 salts 10{4,4,8} and 10{4,4,11}, respective-
quinolone aldehydes 6{1–6} with 4-oxo-4H-chromene-3- ly, precipitated from DCM as purple solids. Both salts were
carbaldehyde (6{8}), 6-fluoro-4-oxo-4H-chromene-3-carbalde- studied in detail by 1D and 2D (COSY, DEPT, HSQC, and
hyde (6{9}), and 9H-fluorene-2-carbaldehyde (6{10}), respec- HMBC) NMR. Restricted rotation of the N-methylindole
tively (Scheme 7 and Figure 1).
moiety is clearly deduced from 1H NMR for both methylium
salts by broadening the pair of protons at δ 8.82/7.43 and 8.62/
Focusing our attention on the synthesis of diversely substituted 6.85 ppm, respectively (Figure 5, Figure 6 and Supporting
tris(heteroaryl)methane triads of type 9 via a three-component Information File 1). Assignments of the quaternary carbons in-
procedure, the approach described in Table 1, entry 2 was cluding the formal carbocation centers were made by HMBC
adopted, and the method was extended to a variety of indoles 1, correlations.
quinoline-/quinolone- and chromene aldehydes 6, and hydroxy-
coumarins 7 as illustrated in Schemes 3–5, leading to a set of NMR data suggest that the positive charge is more effectively
novel tris(heteroaryl)methane triads 9{1,1,1} to 9{6,4,1}, as delocalized into the indole rings. The GIAO-NMR data show
shown in Figure 2.
the same general trend, as evidenced by the 13C Δδ chemical
shifts, with largest charge locations at the conjugated carbon of
Structures of the newly obtained triads 8 and 9 were ascer- the indole ring (Figure S2, Supporting Information File 1). The
tained by 1D and 2D NMR spectroscopy and by EIMS, DFT-optimized structures of methylium-PF6 salts 10{4,4,8}
elemental analysis, and HRMS (see experimental section and and 10{4,4,11} are shown in Figure 7 and Figure 8, where close
Supporting Information File 1). Additionally, single crystals of cation–anion contacts are observed despite significant steric
compound 9{4,7,1} suitable for X-ray analysis were grown crowding. Steric congestion restricts the conjugation of the
from ACN at room temperature. Compound 9{4,7,1} crystal- carbocationic center with the aromatic/heteroaromatic substitu-
lizes in the triclinic space group
(Figure 3). The asym- ents, as evidenced by the bond length shortenings from only
metric unit corresponds to one molecule of 9{4,7,1} and one 0.052 Å to 0.111 Å observed upon hydride abstraction. The op-
molecule of ACN. A packing diagram is shown in Figure S1 timized geometries confirm the restricted rotation of the
(
Supporting Information File 1). Interestingly, the unit cell N-methylindole moiety deduced from experimental 1H NMR
consists of a pair of enantiomers. Within the structure of for both methylium salts as described above (broadening of pair
{4,7,1}, there is a short distance between the quinolone car- of protons at δ 8.82/7.43 and 8.62/6.85 ppm), as this moiety is
9
bonyl and the OH of hydroxycoumarin (H(1)–O(4) 1.740 Å). anchored by the position of the PF6− anion (Figure 7 and
Figure 8). The distance between the formal carbocationic center
The DFT-optimized structure of 9{4,7,1} (Figure 4) confirms and the closest fluorine atom was 3.084 Å in the methylium-PF6
the formation of a highly stable hydrogen bond between the salt 10{4,4,8}, and 3.275 Å in case of the 10{4,4,11} salt.
quinolone carbonyl and the OH of hydroxycoumarin, with a Moreover, C–H···F interactions where also observed, with H···F
O···H bond distance of 1.603 Å. It should be noted that the bond distances between 2.094 Å and 2.575 Å.
hydrogen-bonded conformation is ca. 15 kcal/mol more stable
than other rotamers that do not present this O···H interaction. Conclusion
A facile one-pot method for the three-component synthesis of
In the next phase of the study the possibility to synthesize ternary heteroarylmethane-inspired hybrids is presented, by
crowded tris(heteroaryl/aryl)methylium salts from 8{4,4,8} and coupling quinoline aldehydes, quinolone aldehydes, chromone
8
{4,4,11} was examined. Whereas attempts to cleanly generate aldehydes, and fluorene aldehydes with substituted indoles and
the salts by hydride abstraction with trityl-BF4 were unsuccess- coumarins. The method enabled the synthesis of novel libraries
Scheme 7: Chemset of further aldehydes 6{8–10} for elaboration in the MCR experiments.
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Beilstein J. Org. Chem. 2019, 15, 642–654.
Figure 2: Three-component synthesis of tris(heteroaryl)methane triads 9. aThis product was obtained as an inseparable mixture along compound
8{9,9,6} (see Supporting Information File 1).
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Beilstein J. Org. Chem. 2019, 15, 642–654.
Figure 5: 1D- and 2D-based NMR assignments for methylium-PF6 salt
10{4,4,8}.
Figure 3: Thermal ellipsoid plot (40% probability level) of the
tris(heteroaryl)methane triad 9{4,7,1}.
Figure 6: 1D- and 2D-based NMR assignments for methylium-PF6 salt
0{4,4,11}.
1
of giant (Ar1Ar1Ar2)CH and (Ar1Ar2Ar3)CH triads 8 and 9, re-
spectively, packed with up to three different pharmacophors in a
single molecule. The ability to perform these reactions in
ethanol and even in water, with no catalysts is noteworthy. Rep-
resentative methylium salts generated by ionization with DDQ/
HPF6 exhibited 1H NMR signal broadening reflecting restricted
rotation of the N-methylindole moieties at room temperature.
Figure 4: DFT-optimized structure of 9{4,7,1} triad.
Scheme 8: Synthesis of crowed (Het12Het2/Ar2)C+PF6− salts 10.
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Beilstein J. Org. Chem. 2019, 15, 642–654.
graphic data for the structure has been deposited with the
Cambridge Crystallographic Data Centre as supplementary
publication no: CCDC 1864804. TLC analyses were performed
on silica gel aluminum plates (Merck 60 F254) and spots visual-
ized under UV light. The starting precursors and reagents for
the synthesis of indoles 1{4–9} and quinoline-/quinolone alde-
hydes 6, and the required solvents were purchased from Sigma-
Aldrich, Fluka and Merck (analytical grade reagent), and were
used without further purification.
Catalyzed general procedure for the direct synthesis of
bisindoles 8. A mixture of indole 1 (2.0 equiv), aldehyde 6
(
1.0 equiv), Yb(OTf)3 (5 mol %) and ACN (2 mL), was stirred
at ambient temperature for 6 h until the starting materials 1 and
were no longer detected by TLC. The white precipitate
formed was collected by filtration and washed with cold EtOH
2 × 0.5 mL). No further purification of product 8 was required.
6
(
Alternatively, the more expensive Lewis acid Sc(OTf)3 was
used instead of Yb(OTf)3 with similar behavior and results, al-
though, reactions just took about 3 h. In the case of I2, although,
the reaction worked quite well, the isolation of products 8 re-
quired filtering the colored solid formed and treatment of the
re-dissolved solid in ethyl acetate with sodium thiosulfate to
destroy the excess iodine. Finally, purification of the crude
reaction mixtures by column chromatography was required in
all cases.
Figure 7: Optimized geometry of methylium-PF6 salts 10{4,4,8}.
Uncatalyzed general procedure for the synthesis of prod-
ucts 9. An equimolar mixture of the appropriate indole 1
(
(
1.0 equiv), aldehyde 6 (1.0 equiv), and 4-hydroxycoumarin 7
1.0 equiv) was dissolved in ethanol (2 mL). The solution was
heated to reflux for 3 h until the starting materials 1 and 6 were
no longer detected by TLC. After the solvent was removed
under reduced pressure, the crude reaction mixture was purified
by column chromatography on silica gel, using hexane/EtOAc
Figure 8: Optimized geometry of methylium-PF6 salt 10{4,4,11}.
(
7:3) as eluent. The desired products 9 along with the side-prod-
ucts 8 were isolated and quantified.
Experimental
General. Melting points were measured using a Stuart SMP3 General procedure for the synthesis of carbocation salts
melting point apparatus and are uncorrected. IR spectra were re- 10{4,4,8} and 10{4,4,11}. DDQ (2 equiv) was added to a solu-
corded on a Shimadzu IRAffinity-1 spectrophotometer by ATR tion of 3,3'-(arylmethylene)bis(1-methyl-1H-indoles) 8{4,4,8}
method. 1H and 13C NMR spectra were recorded on Bruker or 8{4,4,11} (50 mg, 1 equiv) in CH2Cl2 (8 mL) at room tem-
Avance 400 and Varian INOVA 500 MHz instruments using perature. After the solution was stirred at the same temperature
DMSO-d6 and CDCl3 as solvents with and without added TMS for 30 min, 60% HPF6 (1 mL) and water (10 mL) were added to
as internal standard. Mass spectra were run on a SHIMADZU- the mixture. The resulting suspension was filtered with suction.
GCMS 2010-DI-2010 spectrometer (equipped with a direct inlet The organic layer was washed with water, dried over MgSO4,
probe) operating at 70 eV. HRMS analyses were performed on and concentrated under reduced pressure. Finally, the crystals
a Finnigan Quantum ultra-AM in electrospray mode using were obtained after simple trituration with Et2O.
methanol as solvent. Single-crystal X-ray data for compound
9
{4,7,1} was collected at 200 K on a Bruker AXS diffrac- Computational methods. Density functional theory (DFT)
tometer upgraded with an APEX II CCD detector. Crystallo- calculations were carried out with the Gaussian 09 program
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Beilstein J. Org. Chem. 2019, 15, 642–654.
suite [66]. Geometries were fully optimized at the B3LYP [67- Acknowledgements
9]/6-311+G(d,p) level. Stationary points were characterized as Authors thank COLCIENCIAS and Universidad del Valle for
6
minima by harmonic vibrational frequency calculations (no financial support—Project Numbers 110665842661 and
imaginary frequencies). NMR chemical shifts were computed CI-71111. L.G. specially thanks COLCIENCIAS for her “Joven
by the GIAO (gauge independent atomic orbitals) [70,71] Investigador” fellowship award. K.K.L. thanks the University
method at the B3LYP/6-311+G(d,p) level. The 1H and of North Florida for the outstanding faculty scholarship and
1
3C NMR chemical shifts were referenced to TMS. GIAO mag- presidential professorship awards, as well as faculty scholar-
netic shielding tensors were 31.88 for 1H, 182.5 for 13C, values ship and UNF Foundation Board grants. G.L.B. acknowledges
related to the GIAO isotropic magnetic susceptibility. funding from CONICET and Secyt-UNC.
X-ray crystallography. Colorless crystals were isolated for ORCID® iDs
9
{4,7,1} from acetonitrile and used for the following X-ray
Jairo Quiroga - https://orcid.org/0000-0002-9451-3063
Kenneth K. Laali - https://orcid.org/0000-0002-0294-844X
Gabriela L. Borosky - https://orcid.org/0000-0001-7660-962X
diffraction studies. A crystal was mounted onto a fiber from
FluorolubeTM and was placed under a liquid N2 cooled stream,
on a Bruker AXS diffractometer updated with an APEX II CCD
detector. The radiation used was graphite monochromatized References
Mo Kα radiation (λ = 0.7107 Å). Lattice determination, data
collection, structure refinement, scaling, and data reduction
were carried out using the APEX2 Version 2014.11 software
package [72,73]. The data were corrected for absorption using
the SCALE program within the APEX2 software suite [72,73].
The structure was solved using SHELXT [74]. This procedure
yielded a number of the C, N and O atoms. Subsequent Fourier
synthesis yielded the remaining atom positions. The hydrogen
atoms are fixed in positions of ideal geometry (riding model)
and refined within the XSHELL software package [75]. The
final refinement of the compound included anisotropic thermal
parameters on all non-hydrogen atoms was performed
using OLEX2-1.2 [76]. The crystal data for compound
1. Dömling, A. Chem. Rev. 2006, 106, 17–89. doi:10.1021/cr0505728
2
.
.
Shiri, M. Chem. Rev. 2012, 112, 3508–3549. doi:10.1021/cr2003954
da Silveira Pinto, L. S.; Couri, M. R. C.; de Souza, M. V. N.
Curr. Org. Synth. 2018, 15, 21–37.
3
doi:10.2174/1570179414666170614124053
4.
5.
6.
7.
Mohammadi Ziarani, G.; Moradi, R.; Ahmadi, T.; Lashgari, N.
RSC Adv. 2018, 8, 12069–12103. doi:10.1039/c7ra13321a
Vroemans, R.; Verhaegen, Y.; Dieu, M. T. T.; Dehaen, W.
Beilstein J. Org. Chem. 2018, 14, 2689–2697. doi:10.3762/bjoc.14.246
Shanab, K.; Neudorfer, C.; Schirmer, E.; Spreitzer, H. Curr. Org. Chem.
2013, 17, 1179–1187. doi:10.2174/1385272811317110005
Gu, Y. Green Chem. 2012, 14, 2091–2128. doi:10.1039/c2gc35635j
8. Nair, V.; Thomas, S.; Mathew, S. C.; Abhilash, K. G. Tetrahedron 2006,
62, 6731–6747. doi:10.1016/j.tet.2006.04.081
9.
Podder, S.; Choudhury, J.; Roy, U. K.; Roy, S. J. Org. Chem. 2007, 72,
100–3103. doi:10.1021/jo062633n
3
9
{4,7,1} is given in Table S1, and a packing diagram is shown
1
0.Gomes, R. F. A.; Coelho, J. A. S.; Frade, R. F. M.; Trindade, A. F.;
Afonso, C. A. M. J. Org. Chem. 2015, 80, 10404–10411.
doi:10.1021/acs.joc.5b01875
in Figure S1 [77] (Supporting Information File 1). Crystallo-
graphic data for the structure has been deposited with the
Cambridge Crystallographic Data Centre as supplementary
publication no: CCDC 1864804. Copies of the data can
be obtained on application to the CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK (fax, +44-(0)1223-336033; or email,
deposit@ccdc.cam.ac.uk).
11.Khaksar, S.; Vahdat, S. M.; Gholizadeh, M.; Talesh, S. M.
J. Fluorine Chem. 2012, 136, 8–11. doi:10.1016/j.jfluchem.2012.01.002
1
2.Kumar Das, S.; Shagufta; Panda, G. Tetrahedron Lett. 2005, 46,
097–3102. doi:10.1016/j.tetlet.2005.03.001
3
1
3.Bushby, S. R. M. Toxicity in Chemotherapy. In Experimental
Chemotherapy; Schnitzer, R. J.; Hawking, F., Eds.; Academic Press:
New York, NY, 1963; Vol. 1, pp 25–53. doi:10.1016/c2013-0-12425-7
4.Yamato, M.; Hashigaki, K.; Yasumoto, Y.; Sakai, J.; Luduena, R. F.;
Banerjee, A.; Tsukagoshi, S.; Tashiro, T.; Tsuruo, T. J. Med. Chem.
1
Supporting Information
1
987, 30, 1897–1900. doi:10.1021/jm00393a035
Supporting Information File 1
1
5.Wulff, H.; Miller, M. J.; Hänsel, W.; Grissmer, S.; Cahalan, M. D.;
Chandy, K. G. Proc. Natl. Acad. Sci. U. S. A. 2000, 97, 8151–8156.
doi:10.1073/pnas.97.14.8151
Spectroscopic data for compounds 8 and 9, copies of NMR
spectra and additional Table and Figures.
1
1
1
6.Mibu, N.; Yokomizo, K.; Uyeda, M.; Sumoto, K. Chem. Pharm. Bull.
[
https://www.beilstein-journals.org/bjoc/content/
2003, 51, 1325–1327. doi:10.1248/cpb.51.1325
supplementary/1860-5397-15-60-S1.pdf]
7.Rys, P.; Zollinger, H. Fundamentals of the Chemistry and Application of
Dyes; Wiley-Interscience: New York, NY, 1972.
Supporting Information File 2
8.Aldag, R. Photochromism based on dissociation processes. In
Photochromism: Molecules and Systems; Dürr, H.; Bouas-Laurent, H.,
Eds.; Elsevier: London, 1990.
CIF report for 9{4,7,1}.
[https://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-15-60-S2.pdf]
19.Shchepinov, M. S.; Korshun, V. A. Chem. Soc. Rev. 2003, 32,
170–180. doi:10.1039/b008900l
652

Beilstein J. Org. Chem. 2019, 15, 642–654.
2
0.Baker, L. A.; Sun, L.; Crooks, R. M. Bull. Korean Chem. Soc. 2002, 23,
47–654. doi:10.5012/bkcs.2002.23.5.647
43.Lin, W.; Yuan, L.; Cao, Z.; Feng, J.; Feng, Y. Dyes Pigm. 2009, 83,
14–20. doi:10.1016/j.dyepig.2009.03.006
6
2
1.Sanguinet, L.; Twieg, R. J.; Wiggers, G.; Mao, G.; Singer, K. D.;
Petschek, R. G. Tetrahedron Lett. 2005, 46, 5121–5125.
doi:10.1016/j.tetlet.2005.05.138
44.Khan, M. N.; Pal, S.; Karamthulla, S.; Choudhury, L. H. New J. Chem.
2014, 38, 4722–4729. doi:10.1039/c4nj00630e
45.Oelerich, J.; Roelfes, G. Org. Biomol. Chem. 2015, 13, 2793–2799.
doi:10.1039/c4ob02487g
2
2
2
2.Yu, L.; Li, S.-S.; Li, W.; Yu, S.; Liu, Q.; Xiao, J. J. Org. Chem. 2018, 83,
1
5277–15283. doi:10.1021/acs.joc.8b02549
3.Oikawa, Y.; Hirasawa, H.; Yonemitsu, O. Tetrahedron Lett. 1978, 19,
759–1762. doi:10.1016/0040-4039(78)80037-9
46.Shao, Z.; Xu, L.; Wang, L.; Wei, H.; Xiao, J. Org. Biomol. Chem. 2014,
12, 2185–2188. doi:10.1039/c3ob42582g
1
47.Jennings, J. J.; Bhatt, C. P.; Franz, A. K. J. Org. Chem. 2016, 81,
6211–6222. doi:10.1021/acs.joc.6b00541
4.Lü, C.-W.; Wang, J.-J.; Liu, Y.-H.; Shan, W.-J.; Sun, Q.; Shi, L.
Res. Chem. Intermed. 2017, 43, 943–949.
48.Prabhakar, M.; Reddy, G. N.; Srinu, G.; Manjulatha, K.; Prasad, J. V.;
Kumar, S. P.; Srinivas, O.; Iqbal, J.; Kumar, K. A. Synlett 2010,
947–951. doi:10.1055/s-0029-1219532
doi:10.1007/s11164-016-2675-8
25.Renzetti, A.; Boffa, E.; Colazzo, M.; Gérard, S.; Sapi, J.; Chan, T.-H.;
Nakazawa, H.; Villani, C.; Fontana, A. RSC Adv. 2014, 4,
49.Shiri, M.; Zolfigol, M. A.; Kruger, H. G.; Tanbakouchian, Z. Chem. Rev.
2010, 110, 2250–2293. doi:10.1021/cr900195a
47992–47999. doi:10.1039/c4ra08853k
2
6.Gérard, S.; Renzetti, A.; Lefevre, B.; Fontana, A.; de Maria, P.; Sapi, J.
Tetrahedron 2010, 66, 3065–3069. doi:10.1016/j.tet.2010.02.025
7.Viegas-Junior, C.; Danuello, A.; da Silva-Bolzani, V.; Barreiro, E. J.;
Fraga, C. A. M. Curr. Med. Chem. 2007, 14, 1829–1852.
doi:10.2174/092986707781058805
50.Kottawar, S. S.; Siddiqui, S. A.; Pendalwar, S. S.; Jadhav, W. N.;
Bhusare, S. R. Res. Chem. Intermed. 2014, 40, 2929–2934.
doi:10.1007/s11164-013-1139-7
2
51.Shelke, G. M.; Rao, V. K.; Tiwari, R. K.; Chhikara, B. S.; Parang, K.;
Kumar, A. RSC Adv. 2013, 3, 22346–22352. doi:10.1039/c3ra44693j
52.Appendino, G.; Cicione, L.; Minassi, A. Tetrahedron Lett. 2009, 50,
5559–5561. doi:10.1016/j.tetlet.2009.05.033
2
8.Zhang, S.; Saathoff, J. M.; He, L. Molecular Hybridization: An Emerging
Tool for the Design of Novel Therapeutics for Alzheimer’s Disease. In
Design of Hybrid Molecules for Drug Development; Decker, M., Ed.;
Elsevier: Amsterdam, 2017; pp 219–237.
53.Mousavizadeh, F.; Hekmatshoar, R.; Beheshtiha, S. Y. S.;
Rahnamafar, R. Synth. Commun. 2014, 44, 1483–1491.
doi:10.1080/00397911.2013.862723
doi:10.1016/b978-0-08-101011-2.00008-8
2
3
3
3
9.Rad-Moghadam, K.; Mohseni, M. Monatsh. Chem. 2004, 135,
54.Laali, K. K.; Insuasty, D.; Abonia, R.; Insuasty, B.; Bunge, S. D.
Tetrahedron Lett. 2014, 55, 4395–4399.
8
17–821. doi:10.1007/s00706-003-0138-6
0.Alizadeh, A.; Ghanbaripour, R.; Zhu, L.-G. Tetrahedron 2014, 70,
048–2053. doi:10.1016/j.tet.2014.01.038
1.El-Mekabaty, A.; Mesbah, A.; Fadda, A. A. J. Heterocycl. Chem. 2017,
4, 916–922. doi:10.1002/jhet.2654
doi:10.1016/j.tetlet.2014.05.094
2
55.Ramírez-Prada, J.; Robledo, S. M.; Vélez, I. D.; del Pilar Crespo, M.;
Quiroga, J.; Abonia, R.; Montoya, A.; Svetaz, L.; Zacchino, S.;
Insuasty, B. Eur. J. Med. Chem. 2017, 131, 237–254.
doi:10.1016/j.ejmech.2017.03.016
5
2.Joule, J. A. In Houben-Weyl Methods of Molecular Transformations;
Thomas, E. J., Ed.; Science of Synthesis; Georg Thieme Verlag:
Stuttgart, Germany , 2000; p 10.
56.Abonia, R.; Insuasty, D.; Castillo, J.; Insuasty, B.; Quiroga, J.;
Nogueras, M.; Cobo, J. Eur. J. Med. Chem. 2012, 57, 29–40.
doi:10.1016/j.ejmech.2012.08.039
3
3.Mugnaini, C.; Nocerino, S.; Pedani, V.; Pasquini, S.; Tafi, A.;
De Chiaro, M.; Bellucci, L.; Valoti, M.; Guida, F.; Luongo, L.;
Dragoni, S.; Ligresti, A.; Rosenberg, A.; Bolognini, D.; Cascio, M. G.;
Pertwee, R. G.; Moaddel, R.; Maione, S.; Di Marzo, V.; Corelli, F.
ChemMedChem 2012, 7, 920–934. doi:10.1002/cmdc.201100573
4.Chung, H. J.; Kamli, M. R.; Lee, H. J.; Ha, J. D.; Cho, S. Y.; Lee, J.;
Kong, J. Y.; Han, S.-Y. Biochem. Biophys. Res. Commun. 2014, 445,
57.Insuasty, D.; Abonia, R.; Insuasty, B.; Quiroga, J.; Laali, K. K.;
Nogueras, M.; Cobo, J. ACS Comb. Sci. 2017, 19, 555–563.
doi:10.1021/acscombsci.7b00091
58.Kong, A.; Han, X.; Lu, X. Org. Lett. 2006, 8, 1339–1342.
doi:10.1021/ol060039u
3
59.Meth-Cohn, O.; Narine, B. Tetrahedron Lett. 1978, 19, 2045–2048.
doi:10.1016/s0040-4039(01)94745-8
561–565. doi:10.1016/j.bbrc.2014.02.029
3
5.Rezayan, A. H.; Hariri, S.; Azerang, P.; Ghavami, G.; Portugal, I.;
Sardari, S. Iran. J. Pharm. Res. 2017, 16, 745–755.
60.Meth-Cohn, O.; Narine, B.; Tarnowski, B.
J. Chem. Soc., Perkin Trans. 1 1981, 1520–1530.
doi:10.1039/p19810001520
3
6.Hranjec, M.; Lučić, B.; Ratkaj, I.; Kraljević Pavelić, S.; Piantanida, I.;
Pavelić, K.; Karminski-Zamola, G. Eur. J. Med. Chem. 2011, 46,
61.Oda, M.; Fukuta, A.; Kajioka, T.; Uchiyama, T.; Kainuma, H.;
Miyatake, R.; Kuroda, S. Tetrahedron 2000, 56, 9917–9925.
doi:10.1016/s0040-4020(00)00964-9
2748–2758. doi:10.1016/j.ejmech.2011.03.062
3
3
3
4
4
4
7.Desyatkin, V. G.; Beletskaya, I. P. Synthesis 2017, 49, 4327–4334.
doi:10.1055/s-0036-1589024
See for an example.
8.Karthik, G.; Rajasekaran, T.; Sridhar, B.; Subba Reddy, B. V.
Tetrahedron 2014, 70, 8148–8154. doi:10.1016/j.tet.2014.07.093
9.Jadhav, S. D.; Bakshi, D.; Singh, A. J. Org. Chem. 2015, 80,
62.Ito, S.; Akimoto, K.; Morita, N. In Recent Developments in Carbocation
and Onium Ion Chemistry; Laali, K. K., Ed.; ACS Symposium Series
965; ACS: Washington, DC, 2007; pp 160–183.
10187–10196. doi:10.1021/acs.joc.5b01736
See for DDQ/HPF6 previously employed for generation of
tri(1-azulenyl)methyl cation salts.
0.Shelke, G. M.; Kumar, A. Synthesis 2017, 49, 4321–4326.
doi:10.1055/s-0036-1588181
63.Ito, S.; Morita, N.; Asao, T. Bull. Chem. Soc. Jpn. 1995, 68,
1409–1436. doi:10.1246/bcsj.68.1409
1.Deb, M. L.; Deka, B.; Saikia, P. J.; Baruah, P. K. Tetrahedron Lett.
2017, 58, 1999–2003. doi:10.1016/j.tetlet.2017.04.032
64.Pfeuffer, L.; Mueller, J.; Pindur, U. Chimia 1985, 39, 141–142.
See for 3-indolylmethylethoxycarbenium BF4 salt.
65.Pindur, U.; Mueller, J. Chem.-Ztg. 1986, 110, 333–335.
See for a UV–vis study of diindolylmethylium.
2.Teguh, S. C.; Klonis, N.; Duffy, S.; Lucantoni, L.; Avery, V. M.;
Hutton, C. A.; Baell, J. B.; Tilley, L. J. Med. Chem. 2013, 56,
6200–6215. doi:10.1021/jm400656s
653

Beilstein J. Org. Chem. 2019, 15, 642–654.
6
6.Gaussian 09, Revision E.01; Gaussian, Inc.: Wallingford, CT, 2009.
7.Becke, A. D. J. Chem. Phys. 1993, 98, 5648–5652.
doi:10.1063/1.464913
6
6
6
7
7
7
7
7
7
7
8.Lee, C.; Yang, W.; Parr, R. G. Phys. Rev. B 1988, 37, 785–789.
doi:10.1103/physrevb.37.785
9.Miehlich, B.; Savin, A.; Stoll, H.; Preuss, H. Chem. Phys. Lett. 1989,
1
57, 200–206. doi:10.1016/0009-2614(89)87234-3
0.Wolinski, K.; Hinton, J. F.; Pulay, P. J. Am. Chem. Soc. 1990, 112,
251–8260. doi:10.1021/ja00179a005
8
1.Ditchfield, R. Mol. Phys. 1974, 27, 789–807.
doi:10.1080/00268977400100711
2.APEX II; Bruker AXS, Inc., Analytical X-ray Systems: 5465 East Cheryl
Parkway, Madison WI 53711–5373, USA, 2005.
3.SAINT, Version 6.45A; Bruker AXS, Inc., Analytical X-ray Systems:
5465 East Cheryl Parkway, Madison WI 53711–5373, USA, 2003.
4.Sheldrick, G. M. Acta Crystallogr., Sect. A: Found. Adv. 2015, 71, 3–8.
doi:10.1107/s2053273314026370
5.SHELXTL, V6.12; Bruker AXS, Inc., Analytical X-ray Systems: East
Cheryl Parkway, Madison WI 53711–5373, USA, 2002.
6.Dolomanov, O. V.; Bourhis, L. J.; Gildea, R. J.; Howard, J. A. K.;
Puschmann, H. J. Appl. Crystallogr. 2009, 42, 339–341.
doi:10.1107/s0021889808042726
77.DIAMOND, Bonn, Germany; Crystal Impact GbR, 1999.
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