Regioselective preparation and NMR spectroscopy study of 2-chloro-4-ethoxy-quinoline for the synthesis of 2-((3-aminopropyl)amino)quinolin-4(1H)-one

Article abstract of DOI:10.1002/mrc.4980

Herein, we describe the C4-ethoxylation of 2,4-dichloroquinoline to prepare 2-chloro-4-ethoxy-quinoline (3), which is a prominent intermediate used for the synthesis of 2-substituted quinolones. To achieve this goal, we studied different conditions for the reaction between 2,4-dichloroquinoline and sodium ethoxide. We discovered that the use of 18-crown-6 ether as an additive and dimethylformamide as the reaction solvent allowed us to obtain the desired product 3 in very good yield and selectivity. In addition, a definitive distinction between the C2 and C4 ethoxylation products was achieved using ¹H─¹⁵N heteronuclear multiple bond correlation. Compound 3 is an intermediate used for the synthesis of 2-((3-aminopropyl)amino)quinolin-4(1H)-one, which displays peculiar behavior during ¹H nuclear magnetic resonance analysis, such as the broadening of the H8 singlet and unexpected deuteration at the C8-position. Effort has been dedicated to understand these findings.

Full text of DOI:10.1002/mrc.4980

dos Santos Francisco Paulo (Orcid ID: 0000-0003-1530-9505)
da Costa Jessie (Orcid ID: 0000-0001-6462-8807)
Regioselective preparation and NMR spectroscopy study of 2-chloro-4-ethoxy-quinoline
for the synthesis of 2-((3-aminopropyl)amino)quinolin-4(1H)-one
Pedro Henrique Vasconcelos Vontobel, Rodrigo dos Santos Fuscaldo, Francisco Paulo dos Santos,* and Jessie
Sobieski da Costa*
Institute of Chemistry, Universidade Federal do Rio Grande do Sul, Av. Bento Gonçalves, 9500 Porto Alegre
91501-970 RS (Brazil).
*Corresponding authors: fpsantos@ufrgs.br; jessie.sobieski@ufrgs.br
Abstract:
Herein, we describe the C4-ethoxylation of 2,4-dichloroquinoline to prepare 2-chloro-4-
ethoxy-quinoline (3), which is a prominent intermediate used for the synthesis of 2-
substituted quinolones. To achieve this goal we studied different conditions for the reaction
between 2,4-dichloroquinoline and sodium ethoxide. We discovered that the use of 18-
crown-6 ether as an additive and DMF as the reaction solvent allowed us to obtain the desired
product 3 in very good yield and selectivity. In addition, a definitive distinction between the
C2 and C4 ethoxylation products was achieved using 1H-15N HMBC. Compound 3 is an
intermediate used for the synthesis of 2-((3-aminopropyl)amino)quinolin-4(1H)-one (5),
which displays peculiar behavior during 1H NMR analysis, such as the broadening of the H8
singlet and unexpected deuteration at the C8-position. Effort has been dedicated to
understand these findings.
Keywords: NMR, 1H-15N HMBC, H/D Exchange, Quinolines, Quinolones, Bederocin.
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INTRODUCTION
Quinoline derivatives are useful in a diverse range of applications, including
pharmaceuticals, and are present in several drugs including antimalarial (chloroquine,
mefloquine, etc.), antibacterial (quinolones and fluoroquinolones), and anticancer
(camptothecin, irinotecan, etc.) agents. Among the quinoline derivatives, 2-substituted
quinolones are a class of bioactive compounds,[1–5] which include bederocin,[6] an
antibacterial compound bearing a 2-aminoalkyl side-chain (Figure 1). The synthesis of 2-
substituted quinolones uses 4-alkoxy-2-haloquinolines as the main intermediate (Figure 1),
which are versatile substrates and susceptible to nucleophilic attack by nitrogen, sulfur or
oxygen nucleophiles at the C2-position.
4-Alkoxy-2-haloquinolines have been prepared using different synthetic pathways,
including the one-step monoalkoxy-dehalogenation of 2,4-dihalogenoquinolines,[7] a two-step
sequence via alkylation/deoxy-chlorination of 4-hydroxyquinolin-2(1H)-one,[3] and three-step
route via dialkoxy-dehalogenation/2-dealkoxylation/2-deoxy-chlorination[8] or 2-
dechlorination/4-alkoxylation/2-deoxy-chlorination[9] of 2,4-dichloroquinolines. In fact, the
simplest strategy used to prepare 4-alkoxy-2-haloquinolines is the one-step monoalkoxy-
dehalogenation of 2,4-dihalogenoquinolines, although the regioselectivity of this route has
not been well described or studied. In this context, the present work investigates the
regioselective alkoxylation of 2,4-dihalogenoquinolines. In addition, we have performed a
1H-15N HMBC study to differentiate between the 2- and 4-substitution products. Despite 1H-
15N HMBC being a very useful tool for the structural determination of heterocyclic
compounds, alkaloids etc,[10–12] its application to the structural elucidation of quinoline
derivatives has not been widely explored, however, some examples include Au (III) chloride
compounds with 7,8-benzoquinoline, natural products, and indolo[2,3b]quinolines.[13–16]
RESULTS AND DISCUSSION
Despite the regioselective monoalkoxy-dehalogenation of 2,4-dihalogenoquinolines
being well established to furnish exclusively 2-alkoxy-4-halogenoquinolines,[17] there are no
studies concerning the optimization of the reaction conditions for the selective formation of
their 4-alkoxy-2-halogenoquinoline isomers. Therefore, we decided to study the
regioselective synthesis of 4-ethoxy-2-chloroquinoline 3, which can be used as an
intermediate in the synthesis of 2-substituted quinolones.[4] Compound 3 can be obtained by
the aromatic nucleophilic substitution of 2,4-dichloroquinoline 1 using sodium ethoxide.
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However, this reaction can lead to the formation of the 2- or 4-subsitution products, and the
yield and isomeric ratio of 2 and 3 are heavily influenced by reaction conditions (Table 1).
Initially, aiming for the regioselective synthesis of 3, we were inspired by the work of
Jarvest et al.,[7] who introduced the use of 15-crown-5 to increase the selectivity in the
synthesis of 4-benzyloxy-2-chloro-quinoline, however, the reaction conditions, reagent
stoichiometry, or yield were not reported. The addition of crown ether was used to increase
the amount of 4-substitution by reducing the postulated complexation of sodium by the
quinoline nitrogen atom, which favors substitution at the 2-position.[17] Under these
conditions, the crown ether increased the ratio of 4-substitution to 2-substitution from 1:7 to
1:1. That being so, we chose to use 15-crown-5 in our initial tests (entries 1 and 2). Using 20
mol% of crown ether in THF at 50 °C, a mixture of 2 and 3 was obtained in 83% yield, but
only a slight excess of the isomer of interest 3 was formed. The consumption of starting
material was monitored by TLC and the isomers were easily separated by column
chromatography. When the amount of crown ether was reduced to 10 mol%, there was a
decrease in the yield and selectivity. An increase in the selectivity was observed using 18-
crown-6 (20 mol%) (entry 3), although with no significant increase in yield when compared
to 15-crown-5 (entry 1). No improvement in terms of yield or selectivity was observed upon
increasing the amount of 18-crown-6 to 50 mol% (entry 4). In the absence of this additive,
there was a complete change in the selectivity with the C2-substitution product favored in an
88:12 (2:3) ratio (entry 5). When hexamethylphosphoramide (HMPA, that selectively
solvates cations) was used as an alternative additive no selectivity was observed for any of
the isomers (entry 6). The solvent effect on the reaction yield and selectivity was also studied.
Using toluene, an apolar solvent, we obtained a very slight selectivity on favour of 2, the
undesired isomer (entry 7). Using 1,4-dioxane, an aprotic solvent less polar than THF, a
decrease in the reaction yield and considerable loss of selectivity was observed (entry 8
compared to entry 3). However, the use of acetonitrile, DMSO and ethanol, which are notably
more polar than THF, resulted in an improved yield of 3. Unexpectedly, in DMSO the time
demanded to the complete consumption of the starting material was longer (entry 10). In an
attempt to further improve the selectivity in ethanol, the reaction was performed at ambient
temperature: a slight difference in the selectivity was observed, but the yield was slightly
decreased and a much longer reaction time was required for full substrate consumption (entry
12). For our delight, when DMF was used as the solvent in the presence of 18-crown-6 as the
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additive, both yield and selectivity for 3 were greatly improved (entry 13). A reasonable
explanation for this better result could be done by taking into account the theoretical analysis
on de-solvation of some cations to organic electrolyte solvents by Okoshi et al, which
showed a greater de-solvation energy of sodium to amides when compared to mono-nitriles,
DMSO and ethers, meaning DMF can solvate sodium more efficiently.[18] Also, we observed
a good selectivity in favour of 3 even in the absence of crown ether (entry 14), despite the
result being inferior to that using the additive. Our attempts to decrease the reaction time
and/or to increase the yield by increasing the temperature[19] did not succeed (entry 15
compared to entry 14). As aforementioned, the addition of crown ether is used to increase the
amount of 4-substitution by reducing the postulated complexation between sodium and
quinoline nitrogen. Pursuing an alternative manner to avoid the presence of sodium in the
reaction medium to avoid the need for crown ether, we proposed to perform the reaction in
the absence of sodium ethoxide, expecting the ethanol itself would act as a nucleophile. We
planned to improve the reaction kinetic by adding N,N-dimethyl-aminopyridine (DMAP) to
attack C-4 position providing a better leaving group (the corresponding ammonium cation
bonded), however no reaction was observed and the 2,4-dichloroquinoline was recovered
(entry 16). In this test, triethylamine was used to prevent substrate protonation by HCl
byproduct, since nitrogen protonation would improve attack to C2-position. Although 4-
alkoxy-quinolines were preferentially formed in the presence of K2CO3 as an additive,[20] we
did not have any success when trying to reproduce this protocol using 2,4-dicloroquinoline
and sodium ethoxide. When the reaction was performed employing K2CO3 as additive in
DMF or acetonitrile, the results (entries 17–18) were not satisfactory when compared to that
obtained using crown ether in DMF (entry 13).
Considering the possibility of obtaining the 2- and 4-substitution products, we decided
to carry out a NMR study[17] that successfully allows them to be definitively distinguished
from one another. Although compounds 2 and 3 exhibit different 1H NMR chemical shifts (δ)
corresponding to H3 (δ = 7.02 and 6.71 ppm, respectively), this was not enough to accurately
1
correlate each structure with their spectra. Therefore, we employed H-15N HMBC to obtain
the 4J correlation between the aliphatic hydrogen (H3) and quinolinic nitrogen (N1) atoms,
which can only occur in compound 2. In order to detect 4JH3-N1, we performed experiments to
assess the optimal parameters for the analysis, evaluating the coupling constant J (0.5, 2.0,
and 5.0 Hz) and spectral width (–300–0, 0–200, and 200–600 ppm). The best analysis
conditions were J = 2.0 Hz and a spectral window between –300–0 ppm, in which a signal at
(5, –50 ppm) appears in the sample containing the 2-ethoxy-substituted isomer 2 (Figure 2).
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When the analysis was repeated with a sample containing the 4-ethoxy-substituted isomer 3,
this signal was not detected (Figure 3), as expected, thereby enabling the full spectroscopic
elucidation of 2 and 3.
With the isomer of interest 3 in hand, the next step was the nucleophilic substitution at
C2 using an excess of 1,3-propanediamine to give intermediate 4 in 78% yield after
purification by column chromatography (Scheme 1). Finally, hydrolysis of 4 in an acidic
medium under heating lead to the formation of 5, which presents the quinolone scaffold
bearing an amino-alkyl chain, which is susceptible to subsequent functionalization, such as a
reductive amination reaction with a variety of aldehydes.[4,7]
Despite the fact that several bioactive pharmacophores contain moiety 5, its
spectroscopic characterization is still vague. While Jarvest et al. reported the H8 signal as a
multiplet,[4] in our 1H NMR analysis of 5, we obtained the H8 signal as a broad singlet, which
is unexpected for this kind of aromatic nuclei (Figure 4). The assignment for this signal was
confirmed using several other experiments including 1H-1H COSY, 1H-13C HSQC, and 1H-
13C HMBC (see Supporting Information).
We studied the effect of diluting the NMR sample in order to evaluate whether the
cause of this unusual broadening of H8 signal was due to intermolecular or intramolecular
interactions, as shown in Figure 5. We observed that when the NMR sample solution was
diluted, the H8 signal shape became a distorted doublet or multiplet. All the hydrogen atom
chemical shifts were significantly altered upon diluting the sample concentration from 154 to
77 nM, but were maintained in upon further dilution. These observations indicate the
existence of pi-stacking interactions, in which supramolecular aggregates are favored in the
concentrated sample solution, which affect the aromatic hydrogen atom signals, as reported
by Turcu and Bogdan for the self-association of ciprofloxacin – a quinolone derivative.[21]
We also investigated the temperature effect over the H8 broad signal, and verified its
splitting at about 35oC – the coalescence temperature (Figure 6). These findings could
indicate the rupture of pi-stacking interactions as a consequence of increasing the
temperature, in which supramolecular aggregates are less favored, as also observed on the
dilution effect.
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As shown in Figure 7, 1H-1H ROESY analysis further confirmed these interactions
because several spatial correlations associated with intermolecular interactions were detected,
notably the correlations between the propyl chain aliphatic hydrogen atoms (H9, H10, and
H11) and aromatic hydrogen atoms (H5, H6, H7, and H8), which are distant from one
another in the molecule.
Interestingly, we also observed a reduced integral value for the H3 and H8 signals in
5, which may indicate hydrogen-deuterium exchange promoted by the deuterated solvent. In
order to confirm this reaction, we performed 2H NMR analysis and it was possible to note
that deuteration occurred at H1 and H9, as expected, which are labile hydrogens bonded to
nitrogen atoms (Figure 8). Furthermore, we observed a not so expected D-H exchange at C3,
which has been previously reported by Kurasawa et al. for 2-substituted-4-quinolones in
acidic media.[22] Inspired by the mechanism postulated in this work, we propose the D-H
exchange proceeds via the formation of keto-tautomer II during the reaction between its enol
form and methanol-d4 (Scheme 2).
However, the 2H NMR spectrum of 5 also shows unexpected deuteration at C8. As
depicted in Scheme 3, we propose this exchange takes place through the unfavored formation
of IV, which is generated by nucleophilic attack of the π-system by deuterated methanol,
which causes a disruption in the aromaticity of the benzene ring. The following step involves
the removal of D from IV by the base available in the reaction, which restores the aromaticity
to form V. This proposed mechanism can explain the higher degree of deuteration at C8 when
compared to C3, N1, or N9, since the formation of IV is very slow because of the disruption
to its aromaticity and the removal of H being faster than the removal of D. This causes an
accumulation of C8-deuterated species, something that does not occur at C3, N1, and N9,
because all the steps involved toward deuteration at these positions occur via tautomerization
and will require less activation energy.
CONCLUSIONS
In summary, we have reported a regioselective synthesis of 2-chloro-4-ethoxy-quinoline (3)
starting from 2,4-dichloroquinoline using a simple and efficient protocol. This quinoline
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derivative was efficiently distinguished from its regioisomer 2 using 1H-15N HMBC.
Furthermore, the desired product 2-((3-aminopropyl)amino)quinolin-4(1H)-one (5) was
studied using NMR spectroscopy and some questions aroused from the spectra data, such as
the broadening of the H8 singlet and unexpected deuteration at C8 position. In this context,
we dedicated efforts to postulate some reasonable explanations for the peculiar behavior
shown by 5.
EXPERIMENTAL
Materials
2,4-Dichloroquinoline was prepared according a literature procedure.[23] Sodium
ethoxide and 1,3-propanediamine were purchased from Sigma Aldrich and used as received
without further purification. All reactions were performed under anhydrous conditions, unless
stated otherwise. All the solvents were dried overnight over 3 A molecular sieves prior to
use.[24] Column chromatography was performed with 70-230 mesh SiO2. Thin layer
chromatography (TLC) was performed using supported silica gel GF254, 0.25 mm thickness.
For visualization, TLC plates were placed under UV light 254 nm or ninhydrin solution. All
other reagents were purchased at common chemical suppliers and used as received.
Spectra
All NMR experiments were performed on a Bruker Avance IIIHD 400 spectrometer
equipped with a BBO 5 mm probe with z-gradient operating at 400.06 MHz for 1H, and
100.46 MHz for 13C. Spectra were taken at 298 K under typical conditions for 1H (spectral
width of 6400 Hz with 32 K data points and zero filled to 128 K to give a digital resolution of
0.05 Hz/pt). The 2D-ROSEY experiment used a pre-scan delay of 2.0 s and 256 F1
increments and 4096 data points in the acquisition dimension. Data were processed using a
zero-filling up to 512 and a sine window was applied in both F1 and F2 dimensions prior to
Fourier transformation to given a FID resolution 1.56 Hz. The mixing time (Tm) was 700 ms.
Chemical shifts were reported in parts per million (ppm, δ) and referenced to solvents peaks;
methanol-d4 (3.31 ppm) and CDCl3 (7.26 ppm). For the 1H-1H COSY experiments the
cosygpqf pulse sequence was used. The resulting two-dimensional data were processed using
a QSINE transformation function (implemented in the Topspin3.2 software) in both
dimensions prior to Fourier transformation. For the 1H-15N HMBC experiments the
hmbcgpndqf pulse sequence was used. Pre-scan delay of 7.0 s. The resulting two-dimensional
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data were processed using a SINE transformation function (implemented in the Topspin3.2
software) in both dimensions prior to Fourier transformation. For the 1H-13C HMBC and
HSQC experiments the hmbcetgpl3nd and hsqcedetgpsisp2.2 pulses sequences were used,
respectively. The resulting two-dimensional data were processed using a QSINE
transformation function (implemented in the Topspin3.2 software) in both dimensions prior
to Fourier transformation.
Typical procedure for ethoxylation of 2,4-dichloroquinoline
A mixture of 2,4-dichloroquinoline (0.5 mmol, 99.0 mg), sodium ethoxide (0.6 mmol, 52.0
mg), 18-crown-6 (0.1 mmol, 26.5 mg) and DMF (0.5 mL) was stirred at 50oC for 48 h. After
cooling and removal of the volatiles under reduced pressure, the crude material was purified
by column chromatography (silica gel, hexane/ethyl acetate) to give compounds 2 (0.024
mmol, 5.0 mg, 5%) and 3 (0.451 mmol, 93.7 mg, 90%) as white solids.
4-chloro-2-ethoxyquinoline (2):
White solid; Yield: 5%. 1H NMR (CDCl3, 400 MHz) δ 8.12-8.07 (m, 1H); 7.85-7.81 (m, 1H);
7.66 (ddd, J = 8.3; 7.1; 1.3 Hz, 1H); 7.45 (ddd, J = 8.2; 7.1; 1.1 Hz, 1H); 7.02 (s, 1H); 4.52
(q, J = 7.1 Hz, 1H); 1.44 (t, J = 7.1 Hz, 2H). 13C NMR (CDCl3, 100 MHz) δ 161.7; 147.2;
143.7; 130.5; 127.7; 124.7; 124.1; 123.4; 113.2; 62.2; 14.6. Rf = 0.70 (5% EtOAc/hexanes).
2-chloro-4-ethoxyquinoline (3):
White solid; Yield: 90%. 1H NMR (CDCl3, 400 MHz) 8.16 (dd, J = 8.3; 0.9 Hz, 1H); 7.93 (d,
J = 8.4 Hz, 1H); 7.70 (ddd, J = 8.3; 7.0; 1.3 Hz, 1H); 7.50 (ddd, J = 8.4; 7.0; 0.9 Hz, 1H);
6.71 (s, 1H); 4.26 (q, J = 7.0 Hz, 2H); 1.58 (t, J = 7.0 Hz, 3H). 13C NMR (CDCl3, 100 MHz)
δ 163.1; 151.7; 148.2; 130.9; 128.1; 126.0; 122.2; 120.5; 101.7; 64.9; 14.5. Rf = 0.33 (5%
AcOEt/hexanes).
Preparation of N1-(4-ethoxyquinolin-2-yl)propane-1,3-diamine (4)
A mixture of 2-chloro-4-ethoxyquinoline 3 (0.3 mmol, 62.0 mg) and 1,3-propanediamine (2.4
mmol, 0.22 mL) was stirred at 70oC for 48 h. After cooling and removal of the volatiles under
reduced pressure, the crude material was purified by column chromatography (silica gel,
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dichlorometane/10% ammonium hydroxide in methanolic solution, 94:6) to give compound 4
(0.23 mmol, 56.2 mg) as an yellow solid.
Yellow solid; Yield: 77%. 1H NMR (CD3OD, 400 MHz) δ 7.90 (dd, J = 8.4; 1.4 Hz, 1H);
7.53 (dd, J = 8.3; 0.5 Hz, 1H); 7.45 (ddd, J = 8.4; 7.0; 1.5 Hz, 1H); 7.12 (ddd, J = 8.3; 7.0;
1.4 Hz, 1H); 6.11 (s, 1H); 4.17 (q, J = 7.0 Hz, 2H); 3.52 (t, J = 6.8 Hz, 2H); 2.77 (t, J = 6.8
Hz, 2H); 1.81 (qn, J = 6.8 Hz, 2H); 1.51 (t, J = 7.0 Hz, 3H). 13C NMR (CD3OD, 400 MHz) δ
163.0; 160.7; 149.7; 130.8; 125.4; 122.7; 122.1; 119.0; 91.4; 65.0; 39.6; 39.3; 33.3; 14.8. Rf
= 0.45 (dichlorometane/10% ammonium hydroxide in methanolic solution, 94:6)
Preparation of 2-((3-aminopropyl)amino)quinolin-4(1H)-one (5)
A mixture of N1-(4-ethoxyquinolin-2-yl)propane-1,3-diamine (4) (0.2 mmol, 45.0 mg) and
concentrated HCl aqueous solution (2.2 mL) was refluxed for 24 h. After cooling, the
volatiles were removed under reduced pressure to give compound 5 (0.18 mmol, 54.0 mg) as
a pale yellow solid.
Yellow solid; Yield: 90%. 1H NMR (CD3OD, 400 MHz) δ 8.04 (d, J = 7.5 Hz, 1H); 7.89 (s,
1H); 7.74 (ddd, J = 8.2; 7.5; 1.1 Hz, 1H); 7.45 (t, J = 8.2 Hz, 1H); 6.37 (s, 1H); 3.66 (t, J =
6.9 Hz, 2H); 3.15 (t, J = 6.9 Hz, 2H); 2.13 (qn, J = 6.9 Hz, 2H). 13C NMR (CD3OD, 400
MHz) δ 155.89; 155.86; 138.97; 134.08; 125.93; 124.44; 118.48; 117.88; 40.60; 38.28;
27.70. 2H NMR (CD3OD, 400 MHz) δ 11.97; 8.57; 7.95; 6.38.
Acknowledgments
Thanks are due to the following Brazilian agencies: CNPq (167156/2014-4), CNPq
(421248/2016-5), FAPERGS, FAPESP (2015/08541-6) for partial financial support. This
study was also financed in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível
Superior - Brasil (CAPES) - Finance Code 001.
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Figure 1. Quinoline derivatives.
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Figure 2. 1H-15N HMBC contour map of 2 in CDCl3.
Figure 3. 1H-15N HMBC contour map of 3 in CDCl3.
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Figure 4. 400 MHz 1H NMR spectrum of 5 recorded in CD3OD.
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1
Figure 5. The dilution effect on the signal multiplicity and chemical shifts observed in the H
NMR spectrum of 5.
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Figure 6. The temperature effect on the H8 signal multiplicity observed in the 1H NMR
spectrum of 5.
Figure 7. 1H-1H ROESY contour map of 5.
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Figure 8. 1H and 2H NMR spectra of 5.
Table 1. The reaction of 2,4-dichloroquinoline and sodium ethoxide under different conditions.
Reaction time
Temp.
(oC)
50
Ratio
(2: 3)b
42: 58
44: 56
34: 66
31: 69
88: 12
50: 50
55: 45
47: 53
29: 71
33: 67
38: 62
35: 65
Yield
(%)c
83
Entry
Additive (mol%)
Solvent
(h)a
1
2
15-crown-5 (20)
15-crown-5 (10)
18-crown-6 (20)
18-crown-6 (50)
-
3
THF
THF
3
50
76
3
1
THF
50
84
4
1
THF
50
80
5
1
THF
50
75
6
HMPA (100)
24
2d
2
THF
50
>95
54
7
18-crown-6 (20)
18-crown-6 (20)
18-crown-6 (20)
18-crown-6 (20)
18-crown-6 (20)
18-crown-6 (20)
Toluene
1,4-dioxane
CH3CN
DMSO
EtOH
50
8
50
75
9
2
50
69
10
11
12
72
2
50
90
50
90
48
EtOH
rt
80
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13
14
15
18-crown-6 (20)
-
48
72d
48
DMF
DMF
DMF
50
50
15: 85
33: 67
31: 69
95
65
67
-
reflux
DMAP (10)/
Et3N (100)
K2CO3 (100)
K2CO3 (100)
16e
24
EtOH
50
-
0
17
18
3
3
DMF
50
50
29: 71
50: 50
34
55
CH3CN
aThe consumption of 2,4-dichloroquinoline was monitored by TLC. bDetermined using the 1H NMR spectrum of the crude
product from the integral of the peaks observed at δ = 6.99 and 6.67 ppm.c The combined isolated yield obtained after
purification. dThis reaction time was considered as maximum eThe reaction was performed in the absence of EtONa.
Scheme 1. Synthesis of 5 starting from 2-chloro-4-ethoxy-quinoline (3).
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Scheme 2. The proposed mechanism for deuteration at the C3 position.
Scheme 3. Proposed mechanism for deuteration at the C8 position.
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