Dipolar Bent and Linear Acetylenes Substituted by Cationic Quinolinium and Anionic Benzoates. Formation of Mesomeric Betaines

Article abstract of DOI:10.1021/acs.joc.6b00561

3-Ethynylquinoline was subjected to a Sonogashira-Hagihara reaction with methyl 2-, 3-, and 4-bromobenzoates, respectively, and then N-methylated to give 3-[((methoxycarbonyl)phenyl)ethynyl]-1-methylquinolinium salts (two X-ray analyses). On saponification of the 3- and 4-substituted benzoates, the mesomeric betaines 3- and 4-[(1-methylquinolinium-3-yl)ethynyl]benzoates were formed. By contrast, the 2-benzoate derivative gave either the corresponding (1-oxo-1H-isochromen-3-yl)quinolinium derivative or the mesomeric betaine 2-(1-methylquinolinium-3-yl)-1,3-dioxo-2,3-dihydro-1H-inden-2-ide depending on the reaction conditions. A DFT calculation predicts a transoid conformation of the acetylene bond in the intermediate 2-[(1-methylquinolinium-3-yl)ethynyl]benzoate which is due to a strong hydrogen bond between the carboxylate group and 2H of the quinolinium ring, in addition to a 1,5-interaction between the carboxylate group and the CC triple bond. The bond angles of the transoid CC triple bond were calculated to be 211.6° and 175.1° in vacuo. The corresponding linear triple bond is 50.4 kJ/mol less stable in vacuo according to the calculation, and the N-heterocyclic carbene quinoline-2-ylidene is not formed as a tautomer.

Full text of DOI:10.1021/acs.joc.6b00561

Article
pubs.acs.org/joc
Dipolar Bent and Linear Acetylenes Substituted by Cationic
Quinolinium and Anionic Benzoates. Formation of Mesomeric
Betaines
Andreas Schmidt,*,§ Sviatoslav Batsyts,§ Alexey Smeyanov,§ Tyll Freese,§ Eike G. Hubner,§
̈
and Martin Nieger‡
§Clausthal University of Technology, Institute of Organic Chemistry, Leibnizstrasse 6, D-38678 Clausthal-Zellerfeld, Germany
‡University of Helsinki, Department of Chemistry, Laboratory of Inorganic Chemistry, P.O. Box 55, FIN-00014 University of
Helsinki, Finland
S
* Supporting Information
ABSTRACT: 3-Ethynylquinoline was subjected to a Sonoga-
shira−Hagihara reaction with methyl 2-, 3-, and 4-bromoben-
zoates, respectively, and then N-methylated to give 3-
[((methoxycarbonyl)phenyl)ethynyl]-1-methylquinolinium salts
(two X-ray analyses). On saponification of the 3- and 4-substituted
benzoates, the mesomeric betaines 3- and 4-[(1-methylquinoli-
nium-3-yl)ethynyl]benzoates were formed. By contrast, the 2-
benzoate derivative gave either the corresponding (1-oxo-1H-isochromen-3-yl)quinolinium derivative or the mesomeric betaine
2-(1-methylquinolinium-3-yl)-1,3-dioxo-2,3-dihydro-1H-inden-2-ide depending on the reaction conditions. A DFT calculation
predicts a transoid conformation of the acetylene bond in the intermediate 2-[(1-methylquinolinium-3-yl)ethynyl]benzoate
which is due to a strong hydrogen bond between the carboxylate group and 2H of the quinolinium ring, in addition to a 1,5-
interaction between the carboxylate group and the CC triple bond. The bond angles of the transoid CC triple bond were
calculated to be 211.6° and −175.1° in vacuo. The corresponding linear triple bond is 50.4 kJ/mol less stable in vacuo according
to the calculation, and the N-heterocyclic carbene quinoline-2-ylidene is not formed as a tautomer.
cross-conjugated mesomeric betaines.10 By contrast, the
INTRODUCTION
■
formation of abnormal NHCs (aNHCs)11 from mesomeric
Heterocyclic mesomeric betaines (MB) are compounds which
betaines requires harsh reaction conditions,12 and the same is
can exclusively be formulated by dipolar resonance forms. In
true for remote NHCs12 that are available by other methods.13
these forms, the positive and negative charges are delocalized
The relatively new class of anionic N-heterocyclic carbenes,
within a common π-electron system. Although sydnones1 and
munchnones2 seemingly are among the most prominent
however, can easily be formed starting from different types of
̈
MBs.14 The interesting area of overlap between the classes of
examples, they represent only two variations of several hundred
heterocyclic mesomeric betaines and N-heterocyclic carbenes
different structures of mesomeric betaines, among those 228
was first summarized in review articles.15
different types of mesoionic compounds.3 In 1985, Ollis,
Quinolinium-3-carboxylate (1) (benzotrigonelline, 3QB) is a
typical example of a cross-conjugated mesomeric betaine
Stanforth, and Ramsden proposed a comprehensive classi-
fication system for mesomeric betaines which was accepted
until 2013.4 They distinguished four major classes of
(CCMB) (Scheme 1). It has been studied with respect to
hydrogen-bond formation with mineral acids16 and formation
heterocyclic mesomeric betaines possessing three types of
conjugation, i.e., conjugated (CMB), cross-conjugated
of hydrates.17 It induces cellular arrest in G2 in Pisum sativum18
and was studied as a chemical delivery system of
(CCMB), and pseudo-cross-conjugated mesomeric betaines
metaiodobenzylguanidine (MIBG) to the central nervous
(PCCMB) and ylides which are closely related to CMB. In
system.19 In the resonance forms of 1, the charges are strictly
2013, Ramsden recognized two new classes employing a
connectivity-matrix analysis5 supported by DFT calculations.6
delocalized in separate parts of the π-electron system (I), and
this is characteristic of CCMBs. Additional features of this class
of compounds are also fulfilled. Thus, the quinolinium ring is
joined to the anion through union bonds (“u”) to an unstarred
The classification system is the basis to understanding the
physical and chemical properties of mesomeric betaines, and
this knowledge translates into interesting applications in
materials chemistry,7 synthetic organic chemistry,8 and natural
position of the isoconjugated equivalent of the anionic fragment
product chemistry.9 The distinct classes of mesomeric betaines
(II). This unstarred position is a nodal position of the highest
(MB) also open access to distinct types of N-heterocyclic
carbenes (NHCs). Thus, normal NHCs (nNHCs) can be
Received: March 15, 2016
prepared under relatively mild conditions starting from pseudo-
© XXXX American Chemical Society
A
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Scheme 1. Quinolinium-3-carboxylate as a Typical
Representative of a CCMB
RESULTS AND DISCUSSION
Syntheses and X-ray Crystallographic Characteriza-
tion. We started the synthesis of the target molecules from 3-
bromoquinoline (2), which was subjected to a Sonogashira−
Hagihara coupling under classical conditions to give 2-methyl-
4-(quinolin-3-yl)but-3-yn-2-ol (3) (Scheme 3). Deprotection
■
Scheme 3. Synthesis of Methyl 2-(Quinolinium-3-
ylethynyl)benzoates
occupied molecular orbital (HOMO) (III) which causes a
charge-separation in the ground state of the molecule.20 The
characteristic dipole type of this class of mesomeric betaines
can be dissected from the resonance forms (IV). Formally, the
CCMB quinolinium-3-carboxylate is the carbon dioxide adduct
of the remote N-heterocyclic carbene quinolin-3-ylidene (V),21
which seemingly is less examined than its benzoannelated
derivative pyridin-3-ylidene.22
In continuation of our interest in mesomeric betaines and
heteroaromatic cations in synthesis23 and catalysis,24 we present
here π-electronically extended cross-conjugated heterocyclic
mesomeric betaines (CCMB) possessing an acetylenic spacer
between the charged moieties of the betaine (Scheme 2). The
type of conjugation remains unchanged on insertion of
conjugated spacers into the characteristic dipole type (VI →
VII).
without prior isolation gave 3-ethynylquinoline (4) in 91%
yield by a method developed by us previously.28 This method
employs potassium hydroxide and potassium phosphate in
toluene and results in clean and efficient deprotection reactions.
3-Ethynylquinoline (4) was then subjected to Sonogashira−
Hagihara couplings with a slight excess (10−20%) of the
acetylenes to give the esters 5a−c in moderate to good yields.
We then tested several methylation reactions of the esters 5a−c
to the corresponding salts 6a−c. Methylation was best
accomplished with dimethyl sulfate in toluene under reflux
conditions. The salts 6a−c precipitated as methylsulfates from
the reaction mixtures and were then filtered off and dried in
vacuo. The methylsulfate anion can be detected at 3.37 and
52.8 ppm in the NMR spectra. Methyl triflate in stoichiometric
amounts at low temperatures (0−20 °C) in dichloromethane
was found to give slightly lower yields of the quinolinium salts
as the corresponding triflates. Methyl iodide in boiling acetone/
methanol/acetonitrile gave only low yields of the correspond-
ing iodide after long reaction times up to 72 h so that this
approach was abandoned.
Scheme 2. Insertion of a Spacer Unit into the Union Bond of
CCMB 1
Single crystals of 6a were obtained after an anion exchange to
hexafluorophosphate by slow evaporation of a concentrated
solution in MeCN (Figure 1), as the hexafluorophosphate
crystallized better than the methyl sulfate. The salt crystallized
monoclinic. The triple bond is slightly bent, and bond angles of
174.29(14)° (C3−C9−C10) and 176.92(14)° (C9−C10−
C11) are found. The triple bond has a bond length of
119.56(18) pm, and the adjacent bonds are typical single bonds
[142.92(16) pm/143.28(16) pm].
The role of triple bonds as spacers has been investigated
intensively, e.g., with respect to conjugation,25 electronic
features of substituents,26 and light-emitting efficiencies on
substitution with donor and acceptor groups.27 Due to the
cross-conjugation, however, the triple bonds are thought to play
the role of geometric spacers in the target molecules with
respect to the frontier orbital profile. Nevertheless, some
surprising results are presented here.
B
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Scheme 4. Formation of the Mesomeric Betaines 8a,b
Figure 1. Molecular structure of quinolinium salt 6a (PF6 anion and
solvent acetonitrile omitted for clarity; displacement parameters are
drawn at 50% probability level).
heterocyclic mesomeric betaines (CCMB) as the highest
occupied molecular orbitals (HOMOs) are indeed essentially
located in the carboxylate group, whereas the LUMO is located
in the quinolinium ring as well as in the carboxylate group.
Some HOMO/LUMO profiles are shown in the Supporting
Information.
Single crystals were also obtained of salt 6c after anion
exchange from a hot methanol solution. The compound also
crystallized monoclinic (Figure 2). Bond angles are
On saponification, the ester 6c showed a different behavior.
The oxoisochromene 9 was obtained after addition of an excess
of hydrochloric acid to the reaction mixture followed by
neutralization with sodium bicarbonate (Scheme 5). Com-
Scheme 5. Reactions and Proposed Mechanisms of the
Instable Mesomeric Betaine 8c
Figure 2. Molecular structure of 6c (displacement parameters are
drawn at 50% probability level).
176.66(18)° (C3−C9−C10) and 172.44(17)° (C9−C10−
C11). The triple bond has a length of 119.1(2) pm; the single
bonds were determined to be 143.0(2) pm and 143.5 (2) pm.
Single crystals of the COO−CD3 derivative of 6c (“6c_D”)
were obtained after an anion exchange to hexafluorophosphate
by slow evaporation of concentrated solution in deuterated
MeCN. The salt also crystallized monoclinic. The triple bond
of 6c_D is slightly bent as well, and bond angles of 176.73(18)°
(C3−C9−C10) and 172.35(17)° (C9−C10−C11) are found.
The triple bond has a bond length of 119.8(2) pm, and the
adjacent bonds are typical single bonds, which are 142.9(2) pm
and 143.4(2) pm long.
In contrast to other betaine formations, the ester hydrolysis
of the salts 6a−c to the target betaines 8a−c under acidic
conditions (H2SO4, HCl, H3PO4, HBF4) failed. On treatment
of the salts 6a,b with excess sodium hydroxide in a methanol−
water mixture at elevated temperatures, decomposition to yet
unidentified products occurred. On reaction at room temper-
ature, followed by acidification to pH 3, the carboxylic acids
7a,b precipitated (Scheme 4). The carboxylic acid proton of 7a
can be detected at δ = 13.31 ppm (DMSO-d6). As expected, the
1H NMR chemical shift differences of 2H and 4H of the
quinolinium ring on formation of the carboxylic acids 7a,b from
the corresponding esters are small (Δδ = 0.07−0.15 ppm).
Adjusting the pH value of solutions of the acids 7a,b in
methanol by triethylamine resulted in the formation of the
target betaines 8a,b in very good yields. In the IR spectra of
8a,b, the triple bond stretching band is observable in medium
intensity between 2211 and 2226 cm−1. The calculated frontier
orbitals of 8a confirmed the classification as cross-conjugated
pound 9 proved to be unstable in NMR solution. 2-
Ethynylbenzoic acid derivatives are known to form oxoiso-
chromenes on treatment with HgSO4 in aqueous sulfuric acid,29
PdCl2(MeCN)2,30 AuCl/K2CO3 in MeCN,31 Rh(I) com-
plexes,32 LiOH in water,33 iridium halides,34 iron(III)-
chloride/PhSeSePh,35 and by other methods.
Saponification of the ester 6c under slightly different reaction
conditions in the presence of water gave a dark red solid in 87%
yield, to which the structure of the conjugated mesomeric
betaine 10 was assigned. The most characteristic chemical shift
changes have been observed for the carbonyl carbon atom
which differ considerably in 8a,b (169.5/168.0 ppm) and 10
(189.4 ppm).
We then tried to intercept 8c by a sequence of reactions
beginning with the saponification of 5c followed by N-
methylation. On saponification of 5c with excess of potassium
C
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hydroxide followed by acidification of the reaction mixture,
however, compound 11 precipitated which proved to be almost
insoluble (Scheme 6). Treatment with base gave 12, which
could be characterized spectroscopically by NMR.
Scheme 8. Calculated Properties of the Instable Bent Betaine
8cbent
Scheme 6. Derivatives of the Mesomeric Betaine 10
Compounds 10 and 11 belong to the class of conjugated
heterocyclic mesomeric betaines, as common sites for negative
and positive charges exist in the resonance forms (VIII)
(Scheme 7).4,5,9,15a The positive and negative partial structures
Scheme 7. Characteristics of CMB 10
bond has a bond distance of 168.5 pm and can thus be
characterized as strong36 under these conditions. In addition, a
1,5 interaction between oxygen and Cβ of the triple bond was
calculated, as the distance (271.8 pm) is considerably shorter
than the sum of the van der Waals radii (O, 152 pm; C, 170
pm). As a consequence, the bond length of the bent triple bond
was calculated to be 122.6 pm, and this is longer than the triple
bond of acetylene (118 pm).37 The carbon atom Cα possesses a
negative partial charge, whereas Cβ is slightly positively charged.
Bond lengths, distances, and partial charges of 8c in the vacuum
are shown in Scheme 8. The bent triple bond of 8c influences
the frontier orbital profile in such a way that the HOMO of 8c
possesses a small coefficient of the LUMO at Cβ of the triple
bond.
Nonlinear X−CC linkages are known, and trans-acetylene
and cis-acetylene have been calculated.38 Thus, diethynyl sulfide
has an average bond angle of the S−CC linkage of
176.4(19)°, and a considerable elongation of the triple bond
was ascribed to a decreased contribution from the dipolar
resonance structure CC−S+CC−.39 Deviations from
linearity up to approximately 5° are also seen in S(CN)240 and
1,2-bis[2-[2-(trimethylsilyl)ethynyl]phenyl] ethane-1,2-dione.41
An angle of 170.5° at the primary carbon atom in addition to a
very small bend of 0.7° in the trans mode at the secondary
carbon was found in methyl 2-[(2,6-dimethoxyphenyl)ethynyl]-
benzoate. In this case, the distance between the carbonyl
oxygen atom and the primary carbon atom of the triple bond
were determined to be 282.7(2) pm, indicative of weak 1,5-
interactions.42 According to a literature research concerning
results of single-crystal analyses, the maximum angle of a bent
acetylene was found to be 146.511°,43 whereas the median is
177.082°.
are joined through a starred position (IX) which is an active
position of the HOMO (X).15a,20 The calculated HOMO/
LUMO profile of 10 is shown in the Supporting Information.
Single crystals of 3-(3-hydroxy-1-oxo-1H-inden-2-yl)-1-meth-
ylquinolinium chloride, i.e., of the protonated form of 10, were
obtained from a saturated solution of 10 in a solvent mixture of
methanol, water, and hydrochloric acid. A molecular drawing is
shown in Figure 3.
Figure 3. Molecular structure of 10 + H+ (displacement parameters
are drawn at 50% probability level).
The adoption of the linear conformer 8clinear, which is no
energetic minimum according the calculation, requires ΔE =
50.4 kJ/mol in the vacuum (Scheme 9). We also calculated the
hydrogen bond formation to 4-H of the quinolinium (8c′bent),
which required more than ΔE = 32.7 kJ/mol in vacuo. The
formation of the pyridine-2-ylidene 8cNHC required 51.2 kJ/
mol. In solution, these values change considerably. Formation
of the linear form starting from the bent betaine 8c requires
19.7 kJ/mol in hexane, 18.7 kJ/mol in diethyl ether, 4.7 kJ/mol
in methanol, 2.8 kJ/mol in THF, and 1.2 kJ/mol in water. The
bent betaine 8cbent has a calculated permanent dipole moment
The chemical behavior of the instable betaine 8c can be
understood in the light of results of DFT calculations which
predict that its triple bond adopts a transoid conformation in
the vacuum. The bond angle between Cα of the triple bond and
C3 of the quinolinium ring was calculated to be +211.6° in
vacuo, and the angle Cβ to the benzoate ring was calculated to
be −175.1° (Scheme 8). The angle is inter alia due to an
intramolecular hydrogen bond between the carboxylate’s
oxygen atom and 2H of the quinolinium ring. The hydrogen
D
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radiation (λ = 0.71073 Å) (6a, 6c_D) or Cu Kα radiation (λ =
1.54178 Å) (6c, 10). Direct methods (SHELXS-97)44 or dual space
methods (10) (SHELXD)44 were used for structure solution, and
refinement was carried out using SHELXL-2014 (full-matrix least-
squares on F2).45 Non-hydrogen atoms were refined anisotropically,
and hydrogen atoms were localized by difference electron density
determination and refined using a riding model (H(O) free).
Semiempirical absorption corrections were applied. For 6a and
6c_D, extinction corrections were applied.
Scheme 9. Calculated Energy Differences between the 8cbent
and the Linear Conformer, Its Alternative 8c′bent, and the
Carbene Tautomer 8cNHC
6a: colorless crystals, C20H16NO2·PF6·C2H3N, M = 488.36, crystal
size 0.36 × 0.20 × 0.10 mm, monoclinic, space group P21/c (No. 14),
a = 15.5730(7) Å, b = 8.1725(3) Å, c = 17.7139(8) Å, β =
101.950(2)°, V = 2205.60(16) Å3, Z = 4, ρ(calcd) = 1.471 Mg m−3,
F(000) = 1000, μ(Mo Kα) = 0.197 mm−1, 67004 reflections (2θmax
=
55.2°), 5097 unique [Rint = 0.029], 302 parameters, R1 (for 4628 I >
2σ(I)) = 0.032, wR2 (all data) = 0.089, S = 1.05, largest diff peak and
hole 0.381 and −0.296 e Å−3.
6c: yellow crystals, C20H16NO2·PF6, M = 447.31, crystal size 0.20 ×
0.18 × 0.03 mm, monoclinic, space group P21/n (No. 14), a =
13.8445(5) Å, b = 8.2667(3) Å, c = 17.2086(6) Å, β = 106.117(1)°, V
= 1892.09(12) Å3, Z = 4, ρ(calcd) = 1.570 Mg m−3, F(000) = 912,
μ(Cu Kα) = 1.999 mm−1, 28286 reflections (2θmax = 144.2°), 3717
unique [Rint = 0.029], 273 parameters, R1 (for 3370 I > 2σ(I)) =
0.033, wR2 (all data) = 0.089, S = 1.06, largest diff peak and hole 0.307
and −0.262 e Å−3.
6c_D: colorless crystals, C20H13D3NO2·PF6, M = 450.33, crystal size
0.36 × 0.26 × 0.08 mm, monoclinic, space group P21/n (No. 14), a =
13.8271(8) Å, b = 8.2406(5) Å, c = 17.2704(9) Å, β = 106.370(2)°, V
= 1888.08(19) Å3, Z = 4, ρ(calcd) = 1.584 Mg m−3, F(000) = 912,
μ(Mo Kα) = 0.221 mm−1, 29589 reflections (2θmax = 55.0°), 4338
unique [Rint = 0.040], 274 parameters, R1 (for 3479 I > 2σ(I)) =
0.038, wR2 (all data) = 0.088, S = 1.04, largest diff peak and hole 0.281
and −0.285 e Å−3.
10: orange crystals, C19H14NO2·Cl, M = 323.76, crystal size 0.36 ×
0.08 × 0.02 mm, monoclinic, space group P21/c (No. 14), a =
10.2551(4) Å, b = 6.3701(2) Å, c = 22.6746(8) Å, β = 102.474(2)°, V
= 1446.28(9) Å3, Z = 4, ρ(calcd) = 1.487 Mg m−3, F(000) = 912,
μ(CuKα) = 2.417 mm−1, 19704 reflections (2θmax = 144.2°), 2814
unique [Rint = 0.044], 212 parameters, 1 restraint, R1 (for 2600 I >
2σ(I)) = 0.049, wR2 (all data) = 0.145, S = 1.09, largest diff peak and
hole 0.603 and −0.501 e Å−3.
of 13.8 D, whereas its linear form has a dipole moment of 17.9
D.
CONCLUSIONS
■
Whereas the mesomeric betaines m- and p-[(1-methylquinoli-
nium-3-yl)ethynyl]benzoates are stable and possess an almost
linear triple bond separating the cationic and the anionic part of
the molecule, the corresponding o-benzoate-derived betaine is
unstable and reacts with hydroxide anions to give either an (1-
oxo-1H-isochromen-3-yl)quinolinium derivative or the con-
jugated mesomeric betaine 2-(1-methylquinolinium-3-yl)-1,3-
dioxo-2,3-dihydro-1H-inden-2-ide. A DFT calculation predicts
an unusual transoid conformation of the acetylene bond in the
instable betaine due to a strong hydrogen bond between the
carboxylate group and 2H of the quinolinium ring in addition
to a 1,5-interaction between the carboxylate group and the CC
triple bond. This bent conformation makes the triple bond
highly susceptible to a nucleophilic attack by hydroxide.
CCDC 1455748 (6a), CCDC 1455749 (6c), CCDC 1455750
(6c_D), and 1455751 (10 + H+) contain the supplementary
crystallographic data for this paper. These data can be obtained free
of charge from The Cambridge Crystallographic Data Centre via www.
ccdc.cam.ac.uk/data_request/cif.
Calculations. All density-functional theory (DFT) calculations
were carried out using the Jaguar 8.3.012 software46 running on Linux
2.6.18-238.el5 SMP (x86_64) on five AMD Phenom II X6 1090T
processor workstations (Beowulf-cluster) parallelized with OpenMPI.
MM2-optimized structures were used as starting geometries. Complete
geometry optimizations were carried out on the implemented
LACVP* (Hay−Wadt effective core potential (ECP) basis on heavy
atoms, N31G6* for all other atoms) basis set and with the B3LYP
density functional. All calculated structures were proven to be true
minima by the absence of imaginary frequencies (with the exception of
8c, which is not a minimum). Plots were obtained using Maestro
9.7.012, the graphical interface of Jaguar. Solvent effects were
estimated by help of the Poisson−Boltzmann Finite element method
implemented in Jaguar. Partial charges were obtained with NBO 6.047
from the results of the DFT calculations.
General Procedure for the Preparation of the Methyl
(Quinolin-3-ylethynyl)benzoates 5a−c. The reactions were
carried out under nitrogen atmosphere. A mixture of 5 mmol of 3-
bromoquinoline, 1 mol % of Pd(PPh3)2Cl2, and 2 mol % of CuI was
suspended in 7 mL of dry Et3N with stirring. A sample of 3-
ethynylquinoline (1.05 equiv) in dry Et3N was added dropwise at
ambient temperature. The resulting solutions were then stirred at
reflux temperature until complete conversion was monitored by TLC.
The mixtures were then allowed to cool to room temperature, treated
EXPERIMENTAL SECTION
■
General Considerations. Flash chromatography was performed
with silica gel 60 (0.040−0.063 mm). 1H NMR spectra were recorded
at 400 or 600 MHz.13C NMR spectra were recorded at 100 or 150
MHz, with the solvent peak or tetramethylsilane used as the internal
reference. Multiplicities are described by using the following
abbreviations: s = singlet, d = doublet, t = triplet, q = quartet, and
m = multiplet. Peak assignments were accomplished by analyzing the
results of HMBC-, HSQC-NMR, and HH-NOESY measurements.
Signal orientations in DEPT experiments were described as follows: o
= no signal; + = up (CH, CH3); − = down (CH2). The NMR
numbering is shown in the Supporting Information. MS (EI) were
obtained with a MS/MS quadrupole mass spectrometer. ESIMS
spectra were obtained at 4000 V capillary voltage and 30 V fragmentor
voltage (unless otherwise noted) using a quadrupole MS spectrometer.
Sample were sprayed from MeCN at 300 °C drying gas temperature.
HRMS spectra were obtained with a Fourier transform-ion cyclotron
resonance mass spectrometer. Melting points are uncorrected and
were determined in an apparatus according to Dr. Tottoli. Yields are
not optimized.
Crystal Structure Determinations. The single-crystal X-ray
diffraction studies were carried out at 123(2) K using Mo Kα
E
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with dichloromethane (50 mL), filtered through Celite, and washed
with water. The organic phases were then dried over MgSO4 and
filtered, and the solvents were removed in vacuo. The resulting
residues were finally purified by column chromatography (petroleum
ether: ethyl acetate) to afford the products.
COOCH3), 45.5 (+, NCH3) ppm. IR (ATR): 1721, 1278, 1240, 1215,
1170, 1097, 1057, 1005, 866, 766, 729, 696, 607, 574 cm−1. MS (ESI):
m/z = 302.1 [M]+. HRMS (ESI): m/z calcd for C20H16NO2 [M]+
302.1181, found 302.1183.
3-((3-(Methoxycarbonyl)phenyl)ethynyl)-1-methylquinolinium
Methylsulfate (6b). Yield: 195 mg of a colorless solid, 90%. Mp: 221−
222 °C. 1H NMR (400 MHz, DMSO-d6): δ = 9.91 (s, 1H, 2-H), 9.54
(s, 1H, 4-H), 8.55 (d, J = 8.9 Hz, 1H, 8-H), 8.45 (d, J = 8.9 Hz, 1H, 5-
H), 8.33 (ddd, J = 1.3, 7.0, 8.9 Hz, 1H, 7-H), 8.22 (s, 1H, 2′-H), 8.15−
8.07 (m, 6-H, 4′-H), 7.95 (dt, J = 1.5, 7.7 Hz, 1H, 6′-H), 7.71 (t, J =
7.7 Hz, 1H, 5′-H), 4.66 (s, 3H, NCH3), 3.91 (s, 3H, COOCH3), 3.38
Methyl 4-(Quinolin-3-ylethynyl)benzoate (5a). Yield: 1078 mg of
a brown solid, 75%. Mp: 138−139 °C. 1H NMR (400 MHz, CDCl3 +
TMS): δ = 9.00 (d, J = 2.2 Hz, 1H, 2-H), 8.33 (d, J = 2.2 Hz, 1H, 4-
H), 8.11 (d, J = 8.6 Hz, 1H, 8-H), 8.06 (ddd, J = 1.4, 2.0, 8.3 Hz, 2H,
3′-H, 5′-H), 7.81 (d, J = 8.6 Hz, 1H, 5-H), 7.74 (ddd, J = 1.5, 6.8, 8.6
Hz, 1H, 7-H), 7.65 (ddd, J = 1.4, 2.0, 8.3 Hz, 2H, 2′-H, 4′-H), 7.58
−
(s, 3H, CH3SO4 ) ppm. 13C NMR (100 MHz, DMSO-d6): δ = 165.2
(ddd, J = 1.5, 6.8, 8.6 Hz, 1H, 6-H), 3.94 (s, 3H, COOCH3) ppm. 13
C
(o, COO), 152.2 (+, C2), 148.1 (+, C4), 137.4 (o, C8a), 136.2 (+,
C6′), 135.9 (+, C7), 132.2 (+, C2′), 130.6 (+, C4′), 130.5 (+, C6),
130.4 (o, C4a), 130.3 (+, C5), 129.9 (+, C5′), 128.7 (o, C3′), 121.2
(o, C1′), 119.3 (+, C8), 116.4 (o, C3), 93.4 (o, Cβ), 84.2 (o, Cα),
NMR (100 MHz, CDCl3 + TMS): δ = 166.5 (o, COO), 152.0 (+,
C2), 147.0 (o, C8a), 138.7 (+, C4), 131.7 (+, C2′, C4′), 130.4 (+,
C8), 130.0 (o, C4′), 129.7 (+, C3′, C5′), 129.5 (+, C7), 127.7 (+, C5),
127.5 (+, C6), 127.3 (o, C4a), 127.2 (o, C1′), 116.9 (o, C3), 91.8 (o,
Cα), 89.5 (o, Cβ), 52.3 (+, CH3) ppm. IR (ATR): 3017, 1716, 1276,
1098, 953, 905, 855, 767, 742, 697, 480 cm−1. MS (ESI): m/z = 287.3
[M+]. HRMS (ESI): m/z calcd for C19H14NO2 [M + H]+ 288.1025,
found 288.1022.
Methyl 3-(Quinolin-3-ylethynyl)benzoate (5b). Yield: 1170 mg of
a colorless solid, 86%. Mp: 116−117 °C. 1H NMR (400 MHz, CDCl3
+ TMS): δ = 9.01 (d, J = 2.0 Hz, 1H, 2-H), 8.32 (d, J = 2.0 Hz, 1H, 4-
H), 8.26 (td, J = 0.5, 2.6 Hz, 1H, 2′-H), 8.11 (d, J = 8.6 Hz, 8-H), 8.04
(dt, J = 1.4, 7.8 Hz, 1H, 4′-H), 7.81 (d, J = 8.6 Hz, 1H, 5-H), 7.78−
7.71 (m, 2H, 6′-H, 7-H), 7.58 (ddd, J = 1.3, 6.9, 8.6 Hz, 1H, 6-H), 7.46
(td, J = 0.5, 7.8 Hz, 1H, 5′-H), 3.95 (s, 3H, CH3) ppm. 13C NMR (100
MHz, CDCl3 + TMS): δ = 166.3 (o, COO), 152.0 (+, C2), 147.0 (o,
C8a), 138.5 (+, C4), 135.8 (+, C6′), 132.9 (+, C2′), 130.6 (o, C3′),
130.3 (+, C4′), 129.8 (+, C8), 129.5 (+, C7), 128.7 (+, C5′), 127.7 (+,
C5), 127.4 (+, C6), 127.2 (o, C4a), 123.1 (o, C1′), 117.1 (o, C8a),
91.5 (o, Cα), 87.5 (o, Cβ), 52.4 (+, CH3) ppm. IR (ATR): 2949, 1719,
1485, 1439, 1269, 1262, 1237, 1127, 994, 902, 782, 744, 677, 487, 474,
454 cm−1. MS (ESI): m/z = 287.2 [M]+. HRMS (ESI): m/z calcd for
C19H13NO2 [M]+ 287.0946, found 287.0948.
Methyl 2-(Quinolin-3-ylethynyl)benzoate (5c). Yield: 807 mg of a
light brownish solid, 56%. Mp: 64−65 °C. 1H NMR (400 MHz,
CDCl3 + TMS): δ = 9.05 (d, J = 2.0 Hz, 1H, 2-H), 8.36 (d, J = 2.0 Hz,
1H, 4-H), 8.11 (d, J = 8.6 Hz, 1H, 8-H), 8.02 (dd, J = 1.5, 7.8 Hz, 1H,
6′-H), 7.81 (d, J = 8.6 Hz, 1H, 5-H), 7.76−7.69 (m, 2H, 3′-H, 7-H),
7.60−7.50 (m, 2H, 4′-H, 6-H), 7.42 (td, J = 1.3, 7.8 Hz, 1H, 5′-H),
3.99 (s, 3H, CH3) ppm. 13C NMR (100 MHz, CDCl3 + TMS): δ =
166.5 (o, COO), 152.2 (+, C2), 147.0 (o, C8a), 138.5 (+, C4), 134.2
(+, C5′), 131.9 (o, C2′), 131.8 (+, C3′), 130.7 (+, C4′), 130.2(+, C8),
129.5 (+, C6′), 128.5 (+, C7), 127.7 (+, C5), 127.4 (+, C6), 127.3
(C4a), 123.1 (o, C1′), 117.5 (o, C3), 91.5 (o, Cα), 91.4 (o, Cβ), 52.3
(+, CH3) ppm. IR (ATR): 2952, 1731, 1565, 1485, 1435, 1270, 1250,
1111, 1076, 899, 746, 6923, 471 cm-1. MS (ESI): m/z = 287.3 [M]+.
HRMS (ESI): m/z calcd for C19H14NO2 [M + H]+ 288.1025, found
288.1030.
General Procedure for the Preparation of Salts 6a−c.
Samples of 0.5 mmol of the esters 5a−c were dissolved in toluene
containing 1 drop of nitrobenzene. Then 0.75 mmol of dimethyl
sulfate was added with stirring. Thereafter, the resulting mixture was
stirred at reflux temperature. After completion of the reaction
(controlled by TLC), the solution was cooled, and the crude product
was filtered off, washed with ethyl acetate (3 × 10 mL), and dried to
afford the product.
−
52.7 (+, CH3SO4 ), 52.5 (+, COOCH3), 45.5 (+, NCH3) ppm. IR
(ATR): 3048, 1718, 1440, 1289, 1230, 1139, 1013, 1000, 772, 757,
732, 609, 578, 551, 431 cm−1. MS (ESI): m/z = 302.1 [M]+. HRMS
(ESI): m/z calcd for C20H16NO2 [M]+ 302.1181, found 302.1180.
3-((2-(Methoxycarbonyl)phenyl)ethynyl)-1-methylquinolinium
Methylsulfate (6c). The compound was synthesized according to the
general procedure. Yield: 194 mg of a yellow solid, 93%. Mp: 216−217
°C. The deuterated form 6c_D was prepared as follows: 3-((2-
(methoxycarbonyl)phenyl)ethynyl)-1-methylquinolinium methylsul-
fate (413 mg, 1 mmol) was dissolved in methanol-d4 (5 mL), and
then 40% D2O solution of sodium hydroxide (200 mg) was added
with stirring. The resulting mixture was stirred for 1 h. Then the
solution was precipitated with water solution of NH4PF6 (1 equiv),
filtered, washed with water and ether, and dried in vacuo. Data for 6c:
1H NMR (400 MHz, DMSO-d6): δ = 9.80 (d, J = 1.0 Hz, 1H, 2-H),
9.47 (s, 1H, 4-H), 8.54 (d, J = 9.1 Hz, 1H, 8-H), 8.50 (d, J = 9.1 Hz,
1H, 5-H), 8.32 (ddd, J = 1.5, 7.1, 9.1 Hz, 1H, 6-H), 8.11 (ddd, J = 1.5,
7.1, 9.1 Hz, 1H, 7-H), 8.04 (dd, J = 1.0, 8.0 Hz, 1H, 6′-H), 7.85 (dd, J
= 1.0, 8.0 Hz, 1H, 3′-H), 7.76 (td, J = 1.5, 7.6 Hz, 1H, 4′-H), 7.66 (td,
J = 1.5, 7.6 Hz, 1H, 5′-H), 4.66 (s, 3H, NCH3), 3.96 (s, 3H,
−
COOCH3), 3.36 (s, CH3SO4 ) ppm. 13C NMR (100 MHz, DMSO-
d6): δ = 165.5 (o, COO), 151.9 (+, C2), 148.0 (+, C4), 137.4 (o,
C8a), 136.1 (+, C7), 134.3 (+, C5′), 132.7 (+, C6′), 131.8 (o, C2′),
130.6 (+, C6), 130.5 (+, C4′), 130.4 (+, C5), 130.2 (+, C3′), 128.8 (o,
C4a), 120.7 (o, C1′), 119.2 (+, C8), 116.8 (o, C3), 93.4 (o, Cβ), 87.4
(o, Cα), 52.8 (+, CH3SO4), 52.5 (+, COOCH3), 45.5 (+, NCH3) ppm.
IR (ATR): 2923, 2219, 1737, 1272, 1258, 1133, 1082, 832, 765, 761,
698, 556, 434 cm−1. MS (ESI): m/z = 302.1 [M]+. HRMS (ESI): m/z
calcd for C20H16NO2 [M]+ 302.1188, found 302.1181.
General Procedure for the Ester Hydrolysis. The correspond-
ing salt (1 mmol) was dissolved in methanol (5 mL), and then sodium
hydroxide (1 N in water, 10 equiv) was added with stirring. The
resulting mixture was stirred overnight. The solution was acidified (pH
= 3) and then concentrated in vacuo, and the crude product was
purified by column chromatography with CHCl3−MeOH as eluent.
3-[(4-Carboxyphenyl)ethynyl]-1-methylquinolinium Chloride
1
(7a). Yield: 64 mg of a brownish solid, 92%. Mp: 97−98 °C. H
NMR (400 MHz, DMSO-d6): δ = 9.97 (d, J = 1.2 Hz, 1H, 2-H), 9.55
(s, 1H, 4-H), 8.55 (d, J = 9.0 Hz, 1H, 8-H), 8.47 (d, J = 9.0 Hz, 1H, 5-
H), 8.32 (ddd, J = 1.3, 6.9, 9.0 Hz, 1H, 7-H), 8.10 (t, J = 9.0 Hz, 1H, 6-
H), 8.06 (ddd, J = 1.5, 1.9, 8.3 Hz, 2H, 3′-H, 5′-H), 7.79 (ddd, J = 1.5,
1.9, 8.3 Hz, 2H, 2′-H, 6′-H), 4.67 (s, 3H, CH3) ppm. 13C NMR (100
MHz, DMSO-d6): δ = 166.5 (o, COO), 152.2 (+, C2), 148.2 (+, C4),
137.4 (o, C9), 136.2 (+, C7), 131.9 (+, C2′, C6′), 131.8 (o, C4′),
130.6 (+, C6), 130.4 (+, C5), 129.8 (+, C3′, C5′), 128.7 (o, C4a),
124.7 (o, C1′), 119.2 (+, C8), 116.3 (o, C3), 93.7 (o, Cβ), 85.6 (o,
Cα), 45.4 (+, CH3) ppm. IR (ATR): 3031, 2211, 1695, 1596, 1543,
1520, 1353, 1273, 1253, 1158, 1012, 770, 748, 694, 626, 478, 434
cm−1. MS (ESI): m/z = 288.0 [M]+. HRMS (ESI): m/z calcd for
C19H14NO2 [M]+ 288.1025, found 288.1022.
3-((4-(Methoxycarbonyl)phenyl)ethynyl)-1-methylquinolinium
Methylsulfate (6a). Yield: 186 mg of a brownish solid, 90%. Mp:
1
219−220 °C. H NMR (400 MHz, DMSO-d6): δ = 9.91 (d, J = 1.2
Hz, 1H, 2-H), 9.54 (s, 1H, 4-H), 8.55 (d, J = 9.0 Hz, 1H, 8-H), 8.46
(d, J = 9.0 Hz, 1H, 5-H), 8.33 (ddd, J = 1.3, 7.0, 9.0 Hz, 1H, 6-H),
8.14−8.07 (m, 3H, 4′-H, 2′-H, 6′-H), 7.83 (ddd, J = 1.5, 1.9, 8.2 Hz,
2H, 3′-H, 5′-H), 4.66 (s, 3H, NCH3), 3.90 (s, 3H, COOCH3), 3.37 (s,
−
3H, CH3SO4 ) ppm. 13C NMR (100 MHz, DMSO-d6): δ = 165.5 (o,
COO), 152.2 (+, C2), 148.3 (+, C4), 137.5 (o, C8a), 136.3 (+, C7),
132.1 (+, C2′, C6′), 130.7 (+, C6), 130.5 (o, C4a), 130.4 (+, C5),
129.7 (+, C3′, C5′), 128.7 (o, C4′), 125.2 (C1′), 119.3 (+, C8), 116.2
(o, C3), 93.5 (o, Cβ), 85.9 (o, Cα), 52.8 (+, CH3SO4), 52.5 (+,
3-[(3-Carboxyphenyl)ethynyl]-1-methylquinolinium Chloride
1
(7b). Yield: 209 mg of a brownish solid, 72%. Mp: 247−248 °C. H
NMR (600 MHz, DMSO-d6): δ = 9.99 (s, 1H, 2-H), 9.56 (s, 1H, 4-
H), 8.56 (d, J = 8.9 Hz, 1H, 8-H), 8.48 (d, J = 8.9 Hz, 1H, 5-H), 8.32
F
DOI: 10.1021/acs.joc.6b00561
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(ddd, J = 1.5, 7.0, 8.9 Hz, 1H, 7-H), 8.22 (s, 1H, 2′-H), 8.11 (t, J = 8.9
Hz, 1H, 6-H), 8.08 (dt, J = 1.3, 7.9 Hz, 1H, 4′-H), 7.88 (dt, J = 1.3, 7.9
Hz, 1H, 6′-H), 7.65 (t, J = 7.9 Hz, 1H, 5′-H), 4.67 (s, 3H, CH3) ppm.
13C NMR (150 MHz, DMSO-d6): δ = 166.8 (o, COO), 152.3 (+, C2),
148.1 (+, C4), 137.4 (o, C9), 136.1 (+, C7), 135.1 (+, C6′), 133.0 (o,
C3′), 132.5 (+, C2′), 130.7 (+, C4′), 130.6 (+, C6), 130.4 (+, C5),
129.5 (+, C5′), 128.8 (o, C4a), 120.8 (o, C1′), 119.3 (+, C8), 116.6
(o, C3), 93.7 (o, Cβ), 83.9 (o, Cα), 45.5 (+, CH3) ppm. IR (ATR):
2225, 1705, 1520, 1379, 1213, 1172, 1141, 1057, 1002, 747, 684, 609,
578, 550, 430 cm−1. MS (ESI): m/z = 288.0 [M]+. HRMS (ESI): m/z
calcd for C19H14NO2 [M]+ 288.1025, found 288.1024.
4-((1-Methylquinolinium-3-yl)ethynyl)benzoate (8a). To a sol-
ution of 0.25 mmol (80 mg) of 3-((4-carboxyphenyl)ethynyl)-1-
methylquinolinium in methanol (4 mL) was added 0.3 mmol (0.042
mL) of triethylamine. The resulting mixture was stirred for 15 min and
then dried in vacuo. The residue was chromatographed on silica gel
(MeOH/CHCl3). Yield: 64 mg of a light green solid, 90%, mp 196−
197 °C. 1H NMR (400 MHz, MeOH-d4): δ = 9.67 (s, 1H, 2-H), 9.32
(s, 1H, 4-H), 8.51 (d, J = 8.8 Hz, 1H, 8-H), 8.41 (d, J = 8.8 Hz, 1H, 5-
H), 8.30 (ddd, J = 1.3, 7.0, 8.8 Hz, 1H, 7-H), 8.09 (t, J = 8.8 Hz, 1H, 6-
H), 7.98 (d, J = 8.6 Hz, 2H, 3′-H, 5′-H), 7.61 (d, J = 8.6 Hz, 2H, 2′-H,
6′-H), 4.73 (s, 3H, CH3) ppm. 13C NMR (100 MHz, methanol-d4): δ
= 169.5 (o, COO), 153.2 (+, C2), 149.5 (o, C4), 140.3 (o, C9), 139.1
(o, C4′), 137.5 (+, C7), 132.5 (+, C2′, C6′), 132.0 (+, C7), 131.7 (+,
C5), 130.8 (o, C4a), 130.6 (+, C3′, C5′), 124.0 (o, C1′), 119.9 (+,
C8), 119.5 (o, C3), 96.7 (o, Cβ), 84.6 (o, Cα), 46.4 (+, CH3) ppm. IR
(ATR): 2183, 1584, 1541, 1415, 1385, 1283, 848, 779, 745, 695 cm−1.
MS (ESI): m/z = 288.0 [M + H]+. HRMS (ESI): m/z calcd for
C19H14NO2 [M + H]+ 288.1025, found 288.1022.
3-((1-Methylquinolinium-3-yl)ethynyl)benzoate (8b). To a sol-
ution of 0.5 mmol (162 mg) of 3-((3-carboxyphenyl)ethynyl)-1-
methylquinolinium in methanol (4 mL) was added 0.5 mmol (0.07
mL) of triethylamine. The resulting mixture was stirred for 15 min and
then dried in vacuo. The residue was chromatographed on silica gel
(MeOH/CHCl3). Yield: 120 mg of a light green solid, 84%. Mp: 213-
214 °C. 1H NMR (600 MHz, DMSO-d6): δ = 9.91 (s, 1H, 2-H), 9.51
(s, 1H, 4-H), 8.53 (d, J = 7.6 Hz, 1H, 8-H), 8.44 (d, J = 7.6 Hz, 1H, 5-
H), 8.31 (t, J = 7.6 Hz, 1H, 7-H), 8.22 (s, 1H, 2′-H), 8.10 (t, J = 7.6
Hz, 1H, 6-H), 8.06 (d, J = 7.4 Hz, 1H, 4′-H), 7.77 (d, J = 7.4 Hz, 1H,
6′-H), 7.58 (t, J = 7.4, 1H, 5′-H), 4.65 (s, 3H, CH3) ppm. 13C NMR
(150 MHz, DMSO-d6): δ = 168.0 (o, COO), 152.7 (+, C2), 148.4 (+,
C4), 137.4 (o, C9), 136.1 (+, C7), 135.8 (o, C3′), 133.4 (+, C6′),
132.6 (+, C2′), 130.8 (+, C4′), 130.6 (+, C6), 130.3 (+, C5), 129.0 (+,
C5′), 128.8 (o, C4a), 120.3 (o, C1′), 119.3 (+, C8), 116.7 (o, C3),
94.6 (o, Cβ), 83.5 (o, Cα), 45.5 (+, CH3) ppm. IR (ATR): 2225, 1695,
1558, 1379, 1256, 1223, 1156, 1142, 1029, 760, 636, 516 cm−1. MS
(ESI): m/z = 288.0 [M + H]+. HRMS (ESI): m/z calcd for
C19H14NO2 [M + H]+ 288.1025, found 288.1025.
2-(1-Methylquinolinium-3-yl)-1,3-dioxo-2,3-dihydro-1H-inden-2-
ide (10). 3-((2-(Methoxycarbonyl)phenyl)ethynyl)-1-methylquinoli-
nium methylsulfate (413 mg; 1 mmol) was dissolved in methanol (5
mL), and then sodium hydroxide (1 N in water, 10 equiv) was added
with stirring. The resulting mixture was stirred overnight. The solution
was then acidified (pH = 3) and concentrated in vacuo, and the crude
product was purified by column chromatography with CHCl3/MeOH
1
as eluent. Yield: 249 mg of a red solid, 87%. Mp: >300 °C. H NMR
(600 MHz, DMSO-d6): δ = 10.44 (d, J = 1.5 Hz, 1H, 2-H), 9.74 (s,
1H, 4-H), 8.25 (d, J = 8.8 Hz, 1H, 8-H), 8.19 (d, J = 8.8 Hz, 1H, 5-H),
7.86 (ddd, J = 1.5, 6.7, 8.8 Hz, 1H, 7-H), 7.79 (t, J = 8.8 Hz, 1H, 6-H),
7.44−7.38 (m, 2H, 5′-H, 8′-H), 7.37−7.33 (m, 2H, 5′-H, 6′-H), 4.56
(s, 3H, CH3) ppm. 13C NMR (150 MHz, DMSO-d6): δ = 189.4
(o,C1′, C3′), 145.7 (+, C2), 139.7 (o, C3a′, C18), 133.7 (o, C8a),
132.9 (o, C3), 131.3 (+, C4), 130.8 (+, C5′, C8′), 130.7 (+, C7),
130.1 (o, C4a), 129.1 (+, C6), 129.0 (+, C5), 118.6 (+, C8), 118.4 (+,
C6′, C7′), 97.2 (o, C2′), 45.8 (+, CH3) ppm. IR (ATR): 1599, 1227,
1203, 1160, 1436, 1407, 1373, 1348, 1338, 890, 758, 719, 510 cm−1.
MS (ESI): m/z = 288.0 [M + H]+. HRMS (ESI): m/z calcd for
C19H14NO2 [M + H]+ 288.1025, found 288.1024.
1,3-Dioxo-2-(quinolinium-3-yl)-2,3-dihydro-1H-inden-2-ide (11)/
Sodium 1,3-Dioxo-2-(quinolin-3-yl)-2,3-dihydro-1H-inden-2-ide
(12). Methyl 2-(quinolin-3-ylethynyl)benzoate (19 mmol) was
dissolved in methanol (7 mL), and then potassium hydroxide (1N
in water, 10 equiv) was added with stirring. The resulting mixture was
stirred for 48 h. The solution was then acidified (pH = 1), and
compound 11 precipitated. The product was filtered off, subsequently
washed with water and with ethyl acetate, and finally dried in vacuo.
Yield: 363 mg of an orange solid (70%), mp >300 °C. IR (ATR):
3060, 2440, 2051, 1977, 1929, 1677, 1609, 1559, 1432, 1355, 907, 867,
758, 717, 612, 548, 516, 468, 415 cm−1. MS (ESI): m/z = 272.0 [M −
H]−. HRMS (ESI): m/z calcd for C18H10NO2 [M − H]− 272.0712;
found 272.0711. To obtain a soluble species for NMR experiment, the
salt was neutralized with NaOH in a water−methanol mixture and
dried in vacuo. 1H NMR (600 MHz, methanol-d4): δ = 9.89 (s, 1H, H-
2), 9.04 (s, 1H, H-4), 7.90−7.88 (d, 1H, J = 8.1 Hz, H-8), 7.81−7.80
(d, 1H, J = 8.1 Hz, H-5), 7.55−7.52 (m, 1H, H-7), 7.48−7.46 (m, 1H,
H-6), 7.36−7.32 (m, 4H, H-4′/H-5′/H-6′/H-7′) ppm. 13C NMR (150
MHz, methanol-d4): δ = 193.9 (o, C1′/C3′), 150.9 (+, C2), 144.9
(o,C8a), 141.1 (o, C3a′/C7a′), 132.1 (o, C3), 130.5 (o, C4a), 130.2
(+, C4), 128.7 (+, C5), 128.3 (+, C8), 128.2 (+, C7), 127.3 (+, C6),
119.2 (+, C5′/C6′), 103.3 (o, C2′) ppm.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.6b00561.
■
S
X-ray data for 6a, 6c_D, 6c, and 10 (CIF)
1-Methyl-3-(1-oxo-1H-isochromen-3-yl)quinolinium Chloride (9).
3-((2-(Methoxycarbonyl)phenyl)ethynyl)-1-methylquinolinium meth-
ylsulfate (256 mg, 0.6 mmol) was dissolved in methanol (5 mL), and
then sodium hydroxide (10 equiv) was added with stirring. The
resulting mixture was stirred over a period of 24 h. The solution was
then acidified (pH = 1), followed by neutralization with sodium
bicarbonate, and concentrated in vacuo. The crude product was
purified by column chromatography with CHCl3/MeOH as eluent.
HOMO/LUMO profiles of the ester 5a and of the
mesomeric betaines 8a, 8cbent, and 10; NMR spectra;
details of the DFT calculations (PDF)
AUTHOR INFORMATION
Corresponding Author
*E-mail: schmidt@ioc.tu-clausthal.de.
■
1
Yield: 139.6 mg of a yellow solid, 70%. Mp: >275 °C. H NMR (400
MHz, methanol-d4): δ = 9.99 (d, J = 1.3 Hz, 1H, 2-H), 9.67 (s, 1H, 4-
H), 8.56−8.52 (m, 2H, 5-H, 8-H), 8.35−8.30 (m, 2H, 7-H, 8′-H),
8.13−8.08 (m, 1H, 6-H), 7.95−7.90 (m, 1H, 6′-H), 7.81−7.79 (m,
2H, 4′-H, 5′-H), 7.73−7.68 (m, 1H, 7′-H), 4.56 (s, 3H, CH3) ppm.
13C NMR (150 MHz, methanol-d4): δ = 162.5 (o, C1′), 149.7 (o,
C8a′), 148.8 (+, C2), 148.59 (o, C3′) 143.1 (+, C4), 139,9 (o, C8a),
137.8 (+, C7), 137.0 (o, C6′), 135.6 (o), 133.6 (o), 132.2 (+, C6),
131.3 (+, C7′), 130.68 (+, C8′), 128.5 (+, C4′), 120.1 (+, C8), 107.4
(+, C4′), 46.7 (+, CH3). IR (ATR): 3098, 2836, 1638, 1587, 1565,
1486, 1455, 1363, 1345, 1330, 1320, 1250, 1210, 1172, 1124, 1109,
1074, 1044, 983, 921, 897, 807, 790, 778, 752, 726, 684, 665, 631, 553
cm−1. MS (ESI): m/z = 288.1 [M]+. HRMS (ESI): m/z calcd for
C19H14NO2 [M]+ 288.1025, found 288.1022.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Dr. Gerald Drager, University of Hannover (Germany), is
gratefully acknowledged for measuring the HRMS spectra.
■
̈
REFERENCES
■
(1) (a) Browne, D. L.; Harrity, J. P. Tetrahedron 2010, 66, 553−568.
(b) Gilchrist, T. L. Science of Synthesis; George Thieme, 2004; Vol. 13,
pp 109−126.
G
DOI: 10.1021/acs.joc.6b00561
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(2) Huisgen, R.; Gotthardt, H.; Bayer, H. O. Angew. Chem. 1964, 76,
185; Angew. Chem., Int. Ed. Engl. 1964, 3, 136.
(20) (a) Potts, K. T.; Murphy, P. M.; Kuehnling, W. R. J. Org. Chem.
1988, 53, 2889−2898. (b) Potts, K. T.; Murphy, P. M.; DeLuca, M. R.;
Kuehnling, W. R. J. Org. Chem. 1988, 53, 2898−2910.
(21) Musavi, S. M.; Amani, J.; Noruzi, P. Int. J. Quantum Chem. 2015,
115, 224−230.
(3) (a) Ollis, W. D.; Ramsden, C. A. Adv. Heterocycl. Chem. 1976, 19,
1−122. (b) Ramsden, C. A. Comprehensive Organic Chemistry;
Sammes, P. G., Ed.; Pergamon Press: Oxford, 1979; Vol. 4, pp
1171−1228.
(4) Ollis, W. D.; Stanforth, S. P.; Ramsden, C. A. Tetrahedron 1985,
41, 2239−2329.
(5) Ramsden, C. A. Tetrahedron 2013, 69, 4146−4159.
(6) (a) Ramsden, C. A.; Oziminski, W. P. Tetrahedron 2014, 70,
7158−7165. (b) Oziminski, W. P.; Ramsden, C. A. Tetrahedron 2015,
71, 7191−7198.
(22) (a) Lavorato, D. J.; Terlouw, J. K.; McGibbon, G. A.; Dargel, T.
K.; Koch, W.; Schwarz, H. Int. J. Mass Spectrom. 1998, 179−180, 7−14.
(b) Stander-Grobler, E.; Schuster, O.; Heydenrych, G.; Cronje, S.;
Tosh, E.; Albrecht, M.; Frenking, G.; Raubenheimer, H. G.
Organometallics 2010, 29, 5821−5833.
(23) Schmidt, A.; Rahimi, A.; Gjikaj, M. Synthesis 2009, 2009, 2371−
2378.
(24) Rahimi, A.; Namyslo, J. C.; Drafz, M.; Halm, J.; Hubner, E.;
̈
(7) (a) Gonsior, N.; Mohr, F.; Ritter, H. Beilstein J. Org. Chem. 2012,
8, 390−397. (b) Koch, A.; Jonas, U.; Ritter, H.; Spiess, H. W.
Tetrahedron 2004, 60, 10011−10018. (c) Theis, A.; Menges, B.;
Mittler, S.; Mierzwa, M.; Pakula, T.; Ritter, H. Macromolecules 2003,
36, 7520−7526. (d) Tonami, H.; Uyama, H.; Kobayashi, S.; Menges,
B.; Mittler, S.; Theis, A.; Ritter, H. Macromol. Chem. Phys. 2003, 204,
1079−1084.
Nieger, M.; Rautzenberg, N.; Schmidt, A. J. Org. Chem. 2011, 76,
7316−7325.
(25) Thomas, R.; Lakshmi, S.; Pati, S. K.; Kulkarni, G. U. J. Phys.
Chem. B 2006, 110, 24674−24677.
(26) Katsuyama, I.; Chouthaiwale, P. V.; Cui, H.-L.; Ito, Y.; Sando,
A.; Tokiwa, H.; Tanaka, F. Tetrahedron 2013, 69, 4098−4104.
(27) Yamaguchi, Y.; Tanaka, T.; Kobayashi, S.; Wakamiya, T.;
Matsubara, Y.; Yoshida, Z. J. Am. Chem. Soc. 2005, 127, 9332−9333.
(28) Smeyanov, A.; Schmidt, A. Synth. Commun. 2013, 43, 2809−
2816.
(8) (a) Zhang, J.; Franz, M.; Hubner, E.; Schmidt, A. Tetrahedron
̈
2016, 72, 525−531. (b) Guan, Z.; Nieger, M.; Schmidt, A. Eur. J. Org.
̈
Chem. 2015, 2015, 4710−4719. (c) Guan, Z.; Hillrichs, K.; Unlu, C.;
̈
Rissanen, K.; Nieger, M.; Schmidt, A. Tetrahedron 2015, 71, 276−282.
(9) Schmidt, A. Adv. Heterocycl. Chem. 2003, 85, 67−171.
(29) Sakamoto, T.; An-naka, M.; Kondo, Y.; Yamanaka, H. Chem.
Pharm. Bull. 1986, 34, 2754−2759.
(10) (a) Sauvage, X.; Zaragoza, G.; Demonceau, A.; Delaude, L. Adv.
Synth. Catal. 2010, 352, 1934−1948. (b) Voutchkova, A. M.; Feliz, M.;
Clot, E.; Eisenstein, O.; Crabtree, R. H. J. Am. Chem. Soc. 2007, 129,
12834−12846. (c) Voutchkova, A. M.; Appelhans, L. N.; Chianese, A.
R.; Crabtree, R. H. J. Am. Chem. Soc. 2005, 127, 17624−17625.
(d) Thomazeau, C.; Olivier-Bourbigou, H.; Magna, L.; Luts, S.;
Gilbert, B. J. Am. Chem. Soc. 2003, 125, 5264−5265. (e) Sauvage, X.;
Demonceau, A.; Delaude, L. Adv. Synth. Catal. 2009, 351, 2031−2038.
(30) Sashida, H.; Kawamukai, A. Synthesis 1999, 1999, 1145−1148.
(31) Marchal, E.; Uriac, P.; Legouin, B.; Toupet, L.; van de Weghe, P.
Tetrahedron 2007, 63, 9979−9990.
(32) Man, B. Y.-W.; Knuhtsen, A.; Page, M. J.; Messerle, B. A.
Polyhedron 2013, 61, 248−252.
(33) Bellina, F.; Ciucci, D.; Vergamini, P.; Rossi, R. Tetrahedron
2000, 56, 2533−2545.
(34) Li, X.; Chianese, A. R.; Vogel, T.; Crabtree, R. H. Org. Lett.
2005, 7, 5437−5440.
̀
(f) Fevre, M.; Pinaud, J.; Leteneur, A.; Gnanou, Y.; Vignolle, J.; Taton,
D.; Miqueu, K.; Sotiropoulos, J.-M. J. Am. Chem. Soc. 2012, 134,
6776−6784. (g) Bissinger, P.; Braunschweig, H.; Kupfer, T.; Radacki,
K. Organometallics 2010, 29, 3987−3990.
(35) Speranca̧ , A.; Godoi, B.; Pinton, S.; Back, D. F.; Menezes, P. H.;
Zeni, G. J. Org. Chem. 2011, 76, 6789−6797.
(36) Jeffrey, G. A. An Introduction to Hydrogen Bonding; Oxford
University Press, 1997; ISBN 978-0195095494.
(11) (a) Grundemann, S.; Kovacevic, A.; Albrecht, M.; Faller Robert,
̈
J. W.; Crabtree, R. H. Chem. Commun. 2001, 2274−2275. (b) Schuster,
O.; Yang, L.; Raubenheimer, H. G.; Albrecht, M. Chem. Rev. 2009, 109,
3445−3478.
(37) Simonetta, M.; Gavezzotti, A.; Patai, S. In The Chemistry of the
Carbon−Carbon Triple Bond; Wiley: New York, 1978; pp 1−56.
(38) (a) Hougen, J. T.; Merer, A. J. J. Mol. Spectrosc. 2011, 267, 200−
221. (b) Hougen, J. T. J. Mol. Spectrosc. 2012, 278, 41−51.
(39) Matzger, A. J.; Lewis, K. D.; Nathan, C. E.; Peebles, S. A.;
Peebles, R. A.; Kuczkowski, R. L. J. Phys. Chem. A 2002, 106, 12110−
12116.
(12) Dreger, A.; Nieger, M.; Drafz, M. H. H.; Schmidt, A. Z.
Naturforsch., B: J. Chem. Sci. 2012, 67, 359−366.
(13) (a) Lavallo, V.; Dyker, C. A.; Donnadieu, B.; Bertrand, G.
Angew. Chem. 2008, 120, 5491−5494; Angew. Chem., Int. Ed. 2008, 47,
5411−5414. (b) Christl, M.; Engels, B. Angew. Chem. 2009, 121,
1566−1567; Angew. Chem., Int. Ed. 2009, 48, 1538−1539.
(40) Demaison, J.; Wlodarczak, G.; Ruck, H.; Wiedenmann, K. H.;
̈
Rudolph, H. D. J. Mol. Struct. 1996, 376, 399−411.
(41) Sparrow, C. R.; Fronczek, F. R.; Watkins, S. F. Acta Crystallogr.,
Sect. E: Struct. Rep. Online 2012, 68, o2809.
(c) Hanninen, M. H. H.; Peuronen, A.; Tuononen, H. M. Chem. -
̈
Eur. J. 2009, 15, 7287−7291. (d) Han, Y.; Huynh, H. V. Dalton Trans.
2011, 40, 2141−2147.
(42) Smith, G. T.; Howard, A. A. K.; Wallis, J. D. Phys. Chem. Chem.
Phys. 2001, 3, 4501−4507.
(43) Li, Q.; Sue, C.-H.; Basu, S.; Shveyd, A. K.; Zhang, W.; Barin, G.;
Fang, L.; Sarjeant, A. A.; Stoddart, J. F.; Yaghi, O. M. Angew. Chem.
2010, 122, 6903−6907; Angew. Chem., Int. Ed. 2010, 49, 6751−6755.
(44) Sheldrick, G. M. Acta Crystallogr., Sect. A: Found. Crystallogr.
2008, 64, 112−122.
(45) Sheldrick, G. M. Acta Crystallogr. 2015, C71, 3−8.
(46) Jaguar, version 8.3; Schrodinger, Inc.: New York, 2014.
(47) Glendening, E. D.; Badenhoop, J. K.; Reed, A. E.; Carpenter, J.
E.; Bohmann, J. A.; Morales, C. M.; Landis, C. R.; Weinhold, F. NBO
6.0; Theoretical Chemistry Institute, University of Wisconsin:
Madison, WI, 2013.
́
(14) (a) Benhamou, L.; Vujkovic, N.; Cesar, V.; Gornitzka, H.;
Lugan, N.; Lavigne, G. Organometallics 2010, 29, 2616−2630.
(b) Danopoulos, A. A.; Monakhov, K. Yu. Chem. - Eur. J. 2013, 19,
450−455. (c) Liu, M.; Nieger, M.; Schmidt, A. Chem. Commun. 2015,
51, 477−479. (d) Pidlypnyi, N.; Wolf, S.; Liu, M.; Rissanen, K.;
Nieger, M.; Schmidt, A. Tetrahedron 2014, 70, 8672−8680.
(e) Pidlypnyi, N.; Namyslo, J. C.; Drafz, M. H. H.; Nieger, M.;
Schmidt, A. J. Org. Chem. 2013, 78, 1070−1078.
(15) (a) Schmidt, A.; Wiechmann, S.; Freese, T. ARKIVOC 2013, i,
424−469. (b) Schmidt, A.; Dreger, A. Curr. Org. Chem. 2011, 15,
2897−2970.
(16) (a) Barczynski, P.; Szafran, M. Polym. J. Chem. 2009, 83, 1061−
1074. (b) Barczynski, P.; Katrusiak, A.; Koput, J.; Dega-Szafran, Z.;
Szafran, M. J. Mol. Struct. 2009, 918, 39−54.
(17) Barczynski, P.; Katrusiak, A.; Koput, J.; Szafran, M. J. Mol. Struct.
2008, 889, 394−407.
(18) Lynn, D. G.; Lewis, D. H.; Tramontano, W. A.; Evans, L. S.
Phytochemistry 1984, 23, 1225−1228.
(19) Gourand, F.; Mercey, G.; Ibazizen
̀
e, M.; Tirel, O.; Henry, J.;
C. L. J. Med. Chem. 2010, 53, 1281−1287.
Levacher, V.; Perrio; Barre,
́
H
DOI: 10.1021/acs.joc.6b00561
J. Org. Chem. XXXX, XXX, XXX−XXX