Synthesis and structure elucidation of a series of chloroquinoline-2-chalcones by the Doebner–Miller reaction

Full text of DOI:10.1002/mrc.4430

Letter - spectral assignments
Received: 19 August 2015
Revised: 5 February 2016
Accepted: 18 February 2016
Published online in Wiley Online Library
(wileyonlinelibrary.com) DOI 10.1002/mrc.4430
Synthesis and structure elucidation of a series
of chloroquinoline-2-chalcones by the
Doebner–Miller reaction
Kaalin Gopaul and Neil A. Koorbanally*
Keywords: chloroquinoline chalcones; structural elucidation; synthesis
depending on the sample to be purified. The melting points were
measured using a sealed capillary tube in an Electrothermal
Introduction
Quinoline chalcones are a group of compounds in which one of the
phenyl rings of the chalcone backbone is substituted with a quino-
line moiety, where both the phenyl group and the quinoline moiety
are separated by an α,β-unsaturated carbonyl group. The quinoline
moiety can either be on the side of the alkene or the ketone. If syn-
thesised from quinoline carbaldehydes, the quinoline is adjacent to
the alkene, and when formed from quinoline acetophenones, it is
next to the ketone.
IA9100 melting point apparatus. IR spectra were recorded on a
Perkin Elmer Spectrum 100 FT-IR spectrometer with universal
attenuated total reflectance sampling accessory. UV spectra were
obtained on a Shimadzu UV–VIS spectrophotometer in dichloro-
methane and methanol. High-resolution mass data was obtained
using a Waters Micromax LCT Premier TOF-MS instrument, operat-
ing at ambient temperatures, with a sample concentration of
1
13
approximately 1 ppm. The H and C NMR spectra were recorded
The synthesis of quinoline-2-chalcones is rare, and only a few
at 298 K with 5 to 10-mg samples dissolved in 0.5 ml of CDCl in
3
[
1–3]
reports exist in the literature.
-carbaldehydes were synthesised as intermediates, which were
then condensed with acetophenones, leading to quinoline-
-chalcones with the quinoline moiety adjacent to the alkene.
These compounds have shown anticancer activity against lung
In these instances, quinoline-
5-mm NMR tubes using a Bruker Avance 400-MHz NMR spectrom-
1
2
eter (9.4 T; Bruker, Germany) (400.22 MHz for H, 100.63 MHz for
1
1
3
19
C and 376.58 Hz for F). The FID resolution was 0.501 Hz/pt for
13
19
2
H, 0.734 Hz/pt for C and 1.36 Hz/pt for F spectra. Chemical
shifts are reported in ppm and coupling constants (J) in Hz. The
[
2]
[3]
1
13
and breast cancer cells, antileishmanial activity and anti-
H and C chemical shifts of the deuterated solvent were 7.24
and 77.0, respectively, referenced to the internal standard, TMS.
[4]
inflammatory properties. Further to this, a complete NMR
elucidation of these compounds is absent in the literature. The only
assignment made in the literature is that of the trans olefinic
protons, probably because they are an indication that the chalcone
hybrids have been formed.
19
For the F NMR spectra, the chemical shift of trifluorotoluene
(0.05% in CDCl ) was referenced at À62.73. All data was analysed
3
using Bruker TopSpin 3.1 software.
A light yellow plate-like specimen of compound 5k, recrystallized
with hexane and ethyl acetate, with approximate dimensions of
0.150mm× 0.220mm× 0.250mm, was used for the X-ray crystallo-
graphic analysis. The data collection and cell refinement were done
using Bruker APEX2 and SAINT-Plus software respectively. Data
Herein we report the synthesis of 15 new quinoline-2-chalcone
hybrids via the quinoline-2-carbaldehyde and have carried out a
complete structural elucidation of them using 1D and 2D NMR.
The effect of containing a fluorine atom in these compounds is also
discussed, which results in very characteristic NMR spectra. The
manner in which these fluorinated compounds are structurally
[5]
reduction was performed with SAINT-Plus and XPREP. SHELXS-97
[
6]
was used to solve and refine the structure. ORTEP-3 was used
to prepare the graphic for publication. Crystallographic data
(excluding structure factors) for the structure in this paper has
been deposited with the Cambridge Crystallographic Data Centre,
CCDC, 12 Union Road, Cambridge CB21EZ, UK. Copies of the data
can be obtained free of charge on quoting the depository number
CCDC 1416785 (Fax: +44-1223-336-033; E-Mail: deposit@ccdc.
cam.ac.uk, http://www.ccdc.cam.ac.uk).
13
elucidated is also quite unique in that C NMR resonances can be
used to identify proton resonances unambiguously.
Experimental
General experimental procedures
All reagents and chemicals used in this study were purchased from
Sigma-Aldrich via Capital Lab, South Africa and were reagent grade.
All organic solvents were redistilled and dried according to
standard procedures. Thin-layer chromatography was performed
using Merck Kieselgel 60 F254 plates. Crude compounds were
purified with column chromatography using silica gel (60–120 mesh)
as the stationary phase and varying combinations of solvents
*
Correspondence to: Neil A. Koorbanally, School of Chemistry, University of
KwaZulu-Natal, Private Bag X54001, Durban 4000, South Africa. E-mail:
Koorbanally@ukzn.ac.za
School of Chemistry, University of KwaZulu-Natal, Durban, South Africa
Magn. Reson. Chem. (2016)
Copyright © 2016 John Wiley & Sons, Ltd.

K. Gopaul and N. A. Koorbanally
Synthesis
(E)-3-(6-chloroquinolin-2-yl)-1-phenylprop-2-en-1-one (5a) light
yellow crystalline solid; Yield 69%; mp 191–193 °C; IR (neat) υ
max
Preparation of 6-chloro-2-methylquinoline (1)
À1
3
053, 1657, 1586 cm ; λmax (log ε): 229 (4.31), 281 (4.34), 343
+
Crotonaldehyde (157.60 mmol, 12.95 ml) in toluene was added
slowly to a warm solution (~40 °C) of 4-chloroaniline (78.78 mmol,
(4.19); HRMS m/z 316.0501 [M + Na] (calcd. for C18H12NOClNa
316.0505)
10.05 g) in aqueous HCl (Fig. 1). The reaction mixture was refluxed
(E)-3-(6-chloroquinolin-2-yl)-1-(2-fluorophenyl)prop-2-en-1-one
overnight, cooled and the toluene layer discarded. The aqueous
layer was basified and extracted with ethyl acetate, dried over an-
(5b) yellow crystalline solid; Yield 57%; mp 154–156 °C; IR (neat)
À1
υ
max 3087, 1660, 1586 cm ; λmax (log ε): 229 (4.28), 278 (4.27),
19
hydrous MgSO
4
and concentrated. The product was purified by col-
339 (4.17); F NMR (376 MHz, CDCl
3
) δ À110.49; HRMS m/z
+
umn chromatography on silica gel using a mobile phase of hexane:
312.0590 [M + H] (calcd. for C18H12NOClF 312.0591)
ethyl acetate (98:2). Compound 1 was produced in 74% yield.
(E)-3-(6-chloroquinolin-2-yl)-1-(3-fluorophenyl)prop-2-en-1-one (5c)
off-white powder; Yield 73%; mp 195–197 °C; IR (neat) υmax 3077,
Preparation of 6-chloroquinoline-2-carbaldehyde (2)
À1
19
1
660, 1580 cm ; λmax (log ε): 231 (4.28), 283 (4.24), 344 (4.15);
NMR (376 MHz, CDCl
) δ À111.60; HRMS m/z 312.0588 [M + H]
(calcd. for C18 12NOFCl 312.0591)
(E)-3-(6-chloroquinolin-2-yl)-1-(4-fluorophenyl)prop-2-en-1-one
(5d) white powder; Yield 58%; mp 215–216 °C; IR (neat) υmax 2920,
F
+
Selenium dioxide (87.42 mmol, 9.70 g) was added to a solution of 1
3
(58.32 mmol, 10.36g) in 1,4-dioxane and refluxed at 100 °C for
H
15 min (Fig. 1). The reaction was monitored by TLC until comple-
tion. Once cooled, the reaction mixture was filtered through celite,
diluted with water and extracted with ethyl acetate. The organic
À1
19
1661, 1587 cm ; λmax (log ε): 229 (4.30), 281 (4.31), 344 (4.18);
NMR (376 MHz, CDCl
) δ À104.81; HRMS m/z 334.0396 [M + Na]
(calcd. for C18 11NOFClNa 334.0411)
F
+
4
extract was dried over anhydrous MgSO , concentrated and
3
subjected to column chromatography (hexane: ethyl acetate 95:5)
H
which yielded the aldehyde 2 in good yield (82%).
(E)-3-(6-chloroquinolin-2-yl)-1-(2-chlorophenyl)prop-2-en-1-one
(
3
5e) yellow crystalline solid; Yield 58%; mp 134–135 °C; IR (neat) υ
max
General procedure for the synthesis of quinoline chalcones (5a–j)
À1
070, 1665, 1589 cm ; λmax (log ε): 228 (4.24), 276 (4.23), 332 (4.10);
+
Substituted acetophenones (1.044 mmol) were dissolved in
absolute ethanol (20 ml), and 10–15 drops of 40% NaOH (aq) were
added at room temperature whilst stirring. 6-Chloroquinoline-
HRMS m/z 350.0108 [M + Na] (calcd. for C H NOCl Na 350.0115)
18 11 2
(E)-3-(6-chloroquinolin-2-yl)-1-(3-chlorophenyl)prop-2-en-1-one (5f)
off-white powder; Yield 82%; mp 194–196 °C; IR (neat) υ
1664, 1589 cm ; λmax (log ε): 229 (4.34), 284 (4.22), 345 (4.14);
HRMS m/z 328.0298 [M+ H] (calcd. for C H NOCl 328.0296)
3072,
max
À1
2-carbaldehyde (2) (1.044 mmol, 200.0 mg) was then added to the
+
solution and allowed to stir for 10–15 min (Fig. 1). The reaction
mixture was then diluted with ice water which resulted in the
quinoline chalcones precipitating out of solution. The product
was dried under vacuum and recrystallized from ethyl acetate.
18
12
2
(E)-3-(6-chloroquinolin-2-yl)-1-(4-chlorophenyl)prop-2-en-1-one
(5g) light yellow powder; Yield 79%; mp 229–230 °C; IR (neat) υ
3050, 1659, 1585 cm ; λmax (log ε): 228 (4.41), 282 (4.37), 342
max
À1
Figure 1. Synthetic scheme for the 6-chloroquinoline-chalcone hybrids 5a–o. Reagents and conditions: (i) HCl (aq), toluene, reflux, 100 °C; (ii) SeO
,4-dioxane, reflux, 100 °C; (iii) substituted acetophenones (4a–j), 40% NaOH (aq), EtOH, rt; (iv) Prenyl bromide, K CO , acetone, rt; (v) 40% NaOH (aq),
EtOH, rt; (vi) BF Et O, 1,4-dioxane, rt.
2
,
1
2
3
3
2
wileyonlinelibrary.com/journal/mrc
Copyright © 2016 John Wiley & Sons, Ltd.
Magn. Reson. Chem. (2016)

Synthesis and structure elucidation of a series of chloroquinoline-2-chalcones
+
(
3
4.26); HRMS m/z 328.0303 [M+H] (calcd. for C H NOCl
28.0296)
18
12
2
Results and Discussion
Synthesis
(E)-3-(6-chloroquinolin-2-yl)-1-(2-methoxyphenyl)prop-2-en-1-one
(
υ
5h) off-white crystalline solid; Yield 58%; mp 141–143 °C; IR (neat)
The quinoline chalcones (5a–o) were synthesised from
À1
max 1661, 1591 cm ; λmax (log ε): 228 (4.37), 274 (4.24), 327
4-chloroaniline in either three (5a–j), four (5k–m) or five steps
+
2
(4.16); HRMS m/z 346.0597 [M + Na] (calcd. for C19H14NO ClNa
(5n–o) depending on the quinoline chalcone synthesised. These
3
46.0611)
reactions involved the Doebner–Miller addition to crotonaldehdye
under acidic conditions to produce the 6-chloro-2-methylquinoline
(E)-3-(6-chloroquinolin-2-yl)-1-(3-methoxyphenyl)prop-2-en-1-one
(5i) yellow crystalline solid; Yield 80%; mp 155–157 °C; IR (neat) υmax
(1), which was further oxidized to the quinoline carbaldehyde (2)
À1
1
3
663, 1590 cm ; λmax (log ε): 228 (4.38), 330 (4.16); HRMS m/z
using selenium dioxide, before being condensed with various
acetophenones to produce the quinoline-chalcone hybrids (5a–j)
in yields of 57–82% (Fig. 1). The prenylated hybrid molecules
+
24.0790 [M + H] (calcd. for C19
2
H15NO Cl 324.0791)
(E)-3-(6-chloroquinolin-2-yl)-1-(4-methoxyphenyl)prop-2-en-1-one
(5j) off white powder; Yield 68%; mp 183–184 °C; IR (neat) υmax
5k–m were synthesised by prenylating the hydroxy group of the
À1
1
655, 1590 cm ; λmax (log ε): 229 (4.37), 280 (4.30), 330 (4.23);
acetophenone prior to being condensed with the quinoline
carbaldehyde in a Claisen–Schmidt condensation with good yields
+
HRMS m/z 346.0600 [M + Na] (calcd. for C19
2
H14NO ClNa 346.0611)
(72–90%), higher than when the electron withdrawing fluoro and
Preparation of prenylated chalcones (5k–m)
chloro groups were present at the same position (Fig. 1). An
attempt to deprenylate these compounds was only successful for
the meta and para prenylated quinolines (5l–m), yielding the
Prenyl bromide (11.02mmol) was added to a stirred solution of the
respective hydroxy acetophenones (7.35 mmol) and CO
14.69 mmol, 2.03g) in dry acetone. The solution was refluxed at
K
2
3
3′- and 4′-hydroxyquinoline-chalcone hybrids (5n–o). These
(
hydroxy quinoline chalcone hybrids could not be synthesised from
the hydroxyacetophenones directly, possibly because of interfer-
ence from the acidic hydroxyl group. Deprenylation of 5k was
unsuccessful, and as such the 2-hydroxyquinoline chalcone hybrid
was the only compound of the series that was not synthesised.
Quinoline chalcones bearing substituents at C-4′ were found to
have higher melting points than compounds with substituents at
C-2′ and C-3′. This could be because of stronger intermolecular
forces and better packing of the molecules. The hydroxylated
chalcones displayed the highest melting points of the series,
thought to be because of intermolecular hydrogen bonding
6
0 °C for 2 h. The reaction mixture was then filtered to remove
unreacted K CO and the filtrate concentrated and dried under
vacuum, yielding the prenylated acetophenones (4k–m) in excellent
yields (80–99%) (Fig. 1). These prenylated acetophenones
2
3
(1.04 mmol) were then condensed with 6-chloroquinoline-
2
-carbaldehyde (2) (1.04 mmol, 200.0 mg) as above to yield the
chalcones 5k–m in yields of 72–90%.
Deprenylation of chalcones 5l and 5m
Chalcones 5l (0.53 mmol, 200.9 mg) and 5m (0.53 mmol, 201.4 mg)
were deprenylated by the addition of BF -OEt (0.810 mmol) to the
(Table 1).
3
2
chalcones in 1,4-dioxane (30 ml) at room temperature. The reaction
mixture was stirred overnight after which it was diluted with water
and extracted with ethyl acetate. The organic layer was dried over NMR Structural Elucidation
anhydrous MgSO and concentrated. The crude extract was
subjected to column chromatography (hexane: ethyl acetate,
0:20) yielding the deprotected chalcones (5n and 5o) in moderate
yields of between 46 and 55% (Fig. 1).
E)-3-(6-chloroquinolin-2-yl)-1-(2-(3-methylbut-2-enyloxy)phenyl)
4
1
13
The full characterisation ( H and C NMR assignments) of the quin-
oline chalcones (5a–o) are presented in Tables 2–5. Unambiguous
chemical shift assignments were made with the aid of 2D NMR
spectra. The structural elucidation of the non-fluorinated quinoline
chalcones is divided into three parts, the quinoline moiety, the
acetophenone aromatic ring and the α,β-unsaturated moiety
linking the two aromatic units together. The fluorinated
compounds (5b–d) are discussed separately from the other
compounds because their spectra are more complicated because
of coupling with fluorine.
8
(
prop-2-en-1-one (5k) yellow crystalline solid; Yield 72%; mp 96–
À1
97 °C; IR (neat) υmax 1654, 1589 cm ; λmax (log ε): 229 (4.46), 278
+
(
4.18), 327 (4.13); HRMS m/z 378.1268 [M + H] (calcd. for
Cl 378.1261)
E)-3-(6-chloroquinolin-2-yl)-1-(3-(3-methylbut-2-enyloxy)phenyl)
23 2
C H21NO
(
prop-2-en-1-one (5l) yellow crystalline solid; Yield 80%; mp 151–
À1
153 °C; IR (neat) υmax 1663, 1590 cm ; λmax (log ε): 228 (4.46), 275
+
(
C
4.33), 333 (4.24); HRMS m/z 378.1273 [M + H] (calcd. for
Cl 378.1261)
E)-3-(6-chloroquinolin-2-yl)-1-(4-(3-methylbut-2-enyloxy)phenyl)
23
H
21NO
2
Table 1. The difference between the chemical shifts of H-9 and H-10
together with the ratio of the outer to inner resonances for each of
the doublets
(
prop-2-en-1-one (5m) off-white powder; Yield 90%; mp 181–182 °C;
IR (neat) υmax 1655, 1600 cm ; λmax (log ε): 285 (4.36), 343 (4.32);
HRMS m/z 378.1271 [M + H] (calcd. for C23
À1
+
Compound
Δδ (Hz)
Peak ratio (%)
H
21NO
2
Cl 378.1261)
5
5
j
112.76
112.52
90.52
46.32
24.64
71
66
74
59
30
(E)-3-(6-chloroquinolin-2-yl)-1-(3-hydroxyphenyl)prop-2-en-1-one
m
(5n) yellow powder; Yield 46%; mp 224–225 °C; IR (neat) υ
3182,
max
À1
+
5l
1663, 1592 cm ; λmax (log ε): 280 (4.36), 337 (4.27); HRMS m/z
5h
308.0484 [M + H] (calcd. for C H NO Cl 308.0478)
1
8
11
2
5
5
b
e
(E)-3-(6-chloroquinolin-2-yl)-1-(4-hydroxyphenyl)prop-2-en-1-one
a
0
(5o) yellow powder; Yield 55%; mp 236–237 °C; IR (neat) υ
3069,
max
À1
1656, 1580 cm ; λ
(log ε): 278 (4.24), 341 (4.27); HRMS m/z
a
max
Resonances completely coalesced into a singlet.
+
332.0452 [M + Na] (calcd. for C H NO ClNa 332.0454)
1
8
12
2
Magn. Reson. Chem. (2016)
Copyright © 2016 John Wiley & Sons, Ltd.
wileyonlinelibrary.com/journal/mrc

K. Gopaul and N. A. Koorbanally
1
Table 2. H NMR shifts of quinoline chalcones (5a–g)
Pos.
5a
5b
5c
5d
5e
5f
5g
3
4
5
7
8
9
7.65 d
7.69 d
7.65 d
8.11 d
7.80 d
7.67 dd
8.06 d
7.90 d
8.09 d
7.76 d
—
7.64 d
7.68 d
8.09 d
7.78 d
7.64 dd
8.00 d
7.59 s
7.65 d
8.10 d
7.80 d
7.67 dd
8.07 d
7.90 d
8.08 d
8.05 br s
—
7.65 d
8.12 d
7.81 d
7.67 dd
8.06 d
7.90 d
8.12 d
8.04 d
7.49 d
—
8.07–8.12 m
7.79 d
8.09 d
8.10–8.16 m
7.80 d
7.79 d
7.66 dd
8.06 d
7.66 dd
8.04 d
7.67 dd
8.06 d
7.90 d
7.83 d
7.89 d
1
2
3
4
5
6
0
8.13 d
7.89 dd
—
8.14 d
7.59 s
′
8.07–8.12 m
7.51 dd
7.60 dd
7.51 dd
8.07–8.12 m
8.10–8.16 m
7.19 dd
—
—
′
7.18 dd
7.54 dddd
7.26 dd
7.80–7.84 m
7.45 dd
7.42 ddd
7.36 ddd
7.50 dd
′
7.29 ddd
7.49 ddd
7.88 d
7.57 d
7.46 dd
7.96 d
′
7.19 dd
8.10–8.16 m
7.49 d
8.04 d
′
5
5
5
5
5
5
5
a J (Hz): 3,4 = 8.4; 5,7 = 2.2; 7,8 = 9.1; 9,10 = 15.5; 2′,3′ = 7.2; 3′,4′ = 7.2; 4′,5′ = 7.2
b J (Hz): 3,4 = 8.5; 5,7 = 2.3; 7,8 = 9.0; 9,10 = 15.5; 10,2′F = 2.6; 3′,2′F = 8.6; 3′,4′ = 8.5; 4′,5′ = 7.2; 4′,2′F = 5.1; 4′,6′ = 1.8; 5′,6′ = 7.6
c J (Hz): 3,4 = 8.4; 5,7 = 2.2; 7,8 = 9.1; 9,10 = 15.4; 2′,3′F = 9.1; 3′F,4′ = 8.1; 4′,5′ = 8.1; 4′,6′ = 2.4; 3′F,5′ = 5.7; 5′,6′ = 7.7
d J (Hz): 3,4 = 8.7; 5,7 = 2.2; 7,8 = 9.0; 9,10 = 15.4; 2′,3′ = 8.6; 3′,4′F = 8.6; 5′,4′F = 8.6; 5′,6′ = 8.6
e J (Hz): 3,4 = 8.6; 5,7 = 2.3; 7,8 = 9.0; 3′,4′ = 7.9; 4′,5′ = 7.2; 5′,6′ = 7.2; 3′,5′ = 1.5; 4′,6′ = 1.8
f J (Hz): 3,4 = 8.5; 5,7 = 2.1; 7,8 = 9.0; 9,10 = 15.5; 4′,5′ = 7.9; 5′,6′ = 7.8
g J (Hz): 3,4 = 8.6; 5,7 = 2.3; 7,8 = 9.1; 9,10 = 15.4; 2′,3′ = 5′,6′ = 8.6
1
Table 3. H NMR shifts of quinoline chalcones (5h–o)
Pos.
5h
5i
5j
5k
5l
5m
5n
5o
3
4
5
7
8
9
7.67 d
7.67 d
8.13 d
7.81 d
7.66–7.68 m
8.13 d
7.90 d
8.18 d
7.61 dd
—
7.64 d
8.09 d
7.79 d
7.66 dd
8.06 d
7.88 d
8.16 d
8.11 d
6.99 d
—
7.67 d
7.65 d
7.64 d
8.08 d
7.78 d
7.66 dd
8.05 d
7.88 d
8.16 d
8.10 d
6.99 d
—
8.36 d
8.59 d
8.20 d
7.87 dd
8.20 d
7.85 d
8.34 d
7.50 dd
—
8.23 d
8.44 d
8.14 d
7.80 dd
8.08 d
7.76 d
8.30 d
8.09 d
6.93 d
—
8.07 d
8.06 d
8.10 d
7.77 d
7.78 d
7.80 d
7.62–7.65 m
8.01 d
7.63 dd
8.01 d
7.65–7.69 m
8.05 d
7.72 d
7.73 d
7.89 d
1
2
3
4
5
6
0
7.83 d
7.96 d
8.12 d
′
—
—
7.61 dd
—
′
6.99 d
6.99 d
′
7.48 ddd
7.04 dd
7.62–7.65 m
3.90 s
7.15 dd
7.43 dd
7.71 dd
3.89 s
7.45 ddd
7.03 dd
7.69 dd
—
7.15 dd
7.41 dd
7.65–7.69 m
—
7.13 dd
7.40 dd
7.66 d
—
′
6.99 d
8.11 d
3.88 s
6.99 d
8.10 d
—
6.93 d
8.09 d
—
′
OCH
3
12
13
15
16
4.62 d (2H)
5.49 t
4.59 d (2H)
5.50 t
4.59 d
5.48 t
1.69 s (3H)
1.65 s (3H)
1.76 s (3H)
1.80 s (3H)
1.75 s (3H)
1.80 s (3H)
5
5
5
5
5
5
5
5
h J (Hz): 3,4 = 8.6; 5,7 = 2.2; 7,8 = 9.0; 9,10 = 15.8; 3′,4′ = 8.4; 4′,5′ = 7.9; 5′,6′ = 7.5; 4′,6′ = 1.8
i J (Hz): 3,4 = 8.5; 5,7 = 2.3; 7,8 = 8.4; 9,10 = 15.5; 4′,5′ = 8.3; 5′,6′ = 7.6; 2′,4′ = 2.2; 4′,6′ = 2.2; 2′,6′ = 2.2
j J (Hz): 3,4 = 8.3; 5,7 = 2.3; 7,8 = 8.9; 9,10 = 15.4; 2′,3′ = 5′,6′ = 8.9
k J (Hz): 3,4 = 8.6; 5,7 = 2.3; 7,8 = 9.1; 9,10 = 15.6; 3′,4′ = 8.5; 4′,5′ = 7.8; 5′,6′ = 7.3; 4′,6′ = 2.1; 12,13 = 6.6
l J (Hz): 3,4 = 8.5; 5,7 = 2.2; 7,8 = 9.1; 9,10 = 15.5; 4′,5′ = 8.3; 5′,6′ = 7.9; 2′,4′ = 2.4; 2′,6′ = 2.4, 12,13 = 6.8
m J (Hz): 3,4 = 8.4; 5,7 = 2.3; 7,8 = 9.1; 9,10 = 15.4; 2′,3′ = 5′,6′ = 8.8; 12,13 = 6.7
n J (Hz): 3,4 = 8.6; 5,7 = 2.3; 7,8 = 7.9; 9,10 = 15.5; 4′,5′ = 8.0; 5′,6′ = 7.9; 2′,4′ = 1.9; 4′,6′ = 2.4; 2′,6′ = 1.9
o J (Hz): 3,4 = 8.6; 5,7 = 2.3; 7,8 = 9.0; 9,10 = 15.7; 2′,3′ = 5′,6′ = 8.7
The quinoline moiety
electron dense than 4-position resulting in H-3 being more upfield
at δ 7.64–7.69 than H-4 at δ 8.07–8.13. As expected, H-3 and H-4
H
H
All the quinolines synthesised in this work were 6-chloro
substituted. H-3 and H-4 are situated on the pyridine ring whilst
H-5, H-7 and H-8 occur on the benzene ring. Because of resonance
effects brought about by the nitrogen, the 3-position is more
are both doublets with J ~8Hz, characteristic of ortho coupling. In
the same way, resonance electron donation involving Cl at C-6
results in H-5 and H-7 being more shielded than H-8 at δH
8.00–8.07. H-5 and H-7 resonate at δ 7.78–7.81 and δ 7.64–7.67
H
H
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Copyright © 2016 John Wiley & Sons, Ltd.
Magn. Reson. Chem. (2016)

Synthesis and structure elucidation of a series of chloroquinoline-2-chalcones
13
Table 4. C NMR shifts of quinoline chalcones (5a–j)
5
a
5b 5c
5d
5e
5f
5g
5h
5i
5j
2
3
4
4
5
6
7
8
8
9
1
1
1
2
3
4
5
6
153.7
122.4
135.9
128.8
126.3
133.2
131.1
131.5
146.8
143.0
127.4
190.5
137.8
128.8
128.7
133.2
128.7
128.8
153.8
121.7
135.8
128.7
126.2
133.3
131.1
131.5
146.8
143.4
153.4
122.5
135.9
128.8
126.3
133.4
131.2
131.5
146.8
143.6
126.8
153.5
122.6
136.0
128.8
126.3
133.3
131.2
131.4
146.7
143.0
126.9
188.8
153.6
121.4
135.9
128.7
126.3
133.5
131.3
131.4
146.7
144.9
131.2
194.0
138.6
131.5
130.4
131.7
127.0
129.4
153.4
122.5
136.0
128.8
126.3
133.4
131.2
131.5
146.8
143.7
126.8
189.1
135.1
128.8
139.4
133.1
130.1
126.8
153.5
122.6
136.0
128.8
126.3
133.3
131.2
131.5
146.8
143.4
126.8
189.2
136.1
130.2
129.1
139.7
129.1
130.2
154.4
121.5
135.7
128.8
126.2
133.1
130.4
131.4
146.7
141.9
132.3
193.0
128.6
158.4
111.7
133.3
120.8
131.0
55.8
153.7
122.4
135.9
128.7
126.3
133.2
131.5
131.1
146.8
143.0
127.4
190.2
139.1
113.0
160.0
119.8
129.7
121.5
55.5
153.9
122.5
135.9
128.7
126.3
133.1
131.1
131.4
146.7
142.1
127.3
188.6
130.7
131.2
114.0
163.8
114.0
131.2
55.5
a
a
0
1
′
131.0 (d, 2.6)
189.2 (d, 2.3)
126.8 (d, 13.1)
161.4 (d, 253.9)
116.7 (d, 22.9)
134.3 (d, 8.8)
124.6 (d, 3.4)
130.7 (d, 6.2)
189.2 (d,1.9)
139.9 (d 6.4)
115.5 (d, 22.4)
163.0 (d, 248.3)
120.2 (d, 21.2)
130.4 (d, 7.6)
124.5 (d, 2.5)
134.1 (d, 2.9)
131.5 (d, 9.4)
115.9 (d, 21.9)
165.9 (d, 255.3)
115.9 (d, 21.9)
131.5 (d, 9.4)
′
′
′
′
′
OCH
3
respectively. The chemical shift and splitting patterns of the
protons on the quinoline moiety remain unaffected by the
substituents on the phenyl ring B and are similar for all quinoline
chalcones 5a–o.
were distinguished by a HMBC correlation from C-8a to H-5 and
H-7 (Fig. 2). The remaining C-6 and C-4a resonances occurred at
similar chemical shifts at δ 133 and δ 129 and were identified
by a HMBC correlation from C-4a to H-3. Thus, using the HSQC
and HMBC spectra, the resonances of the quinoline ring could be
unequivocally assigned.
C
C
The nine carbon resonances of the quinoline ring in CDCl were
3
present at δ 153, 147, 136, 133, 132, 131, 129, 126 and 122 of which
C
five (C-3, C-4, C-5, C-7 and C-8) could be assigned from the HSQC
spectrum because these were protonated. The two most
The α,β-unsaturated carbonyl group
deshielded resonances, C-2 and C-8a, occurring at δ 153 and 147
C
respectively (because they are directly bonded to the nitrogen)
The H-9 and H-10 resonances are easily identified by their large
trans coupling constants of ~15Hz. These resonances can be easily
distinguished by the HMBC correlation of H-9 to C-3. It was
observed that H-9 is more shielded than H-10 even though
resonance effects with the carbonyl group suggest that H-9 should
be the more deshielded resonance. This is true for the carbon
13
Table 5. C NMR shifts of quinoline chalcones (5k–o)
5
k
5l
5m
5n
5o
2
3
4
4
5
6
7
8
8
9
1
1
1
2
3
4
5
6
1
1
1
1
1
154.6
121.3
135.6
128.5
126.2
132.9
130.9
131.4
146.8
141.1
132.7
192.5
128.9
158.1
113.1
133.4
120.8
130.8
65.7
153.7
122.4
135.9
128.7
126.3
133.2
131.1
131.5
146.8
143.0
127.4
190.2
139.1
113.9
159.2
120.4
129.7
121.4
65.1
153.9
122.5
135.8
128.7
126.3
133.0
131.0
131.4
146.7
142.1
127.4
188.6
130.6
131.2
114.6
163.1
114.6
131.2
65.1
153.2
122.0
138.3
129.5
126.8
132.3
131.6
129.2
144.0
140.5
128.7
189.0
138.1
114.7
157.9
120.9
130.0
119.8
154.4
121.8
136.2
128.5
126.6
131.7
130.7
131.3
146.0
141.8
127.6
187.1
128.7
131.4
115.6
162.6
115.6
131.4
resonances, C-9 and C-10 where C-9 is more deshielded at δ
141–143 than C-10 at δ 126–132. The most downfield resonance
in the C NMR spectrum is the carbonyl resonance (C-11) at δ
C
C
13
a
C
188–194, which showed HMBC correlations to H-9, H-10 and H-2′/
6′. The reason that H-9 is more shielded than H-10 is because of a
through space shielding effect by the lone pair on the nitrogen of
the quinoline ring similar to that reported for the pyranochromene
[
7]
a
chalcones in Pawar and Koorbanally.
Considerable second order coupling is observed for H-9 and H-10
in several of the synthesised quinoline chalcones. The distances
(in Hz) between the H-9 and H-10 resonances for the various
substituents on ring B vary, becoming smaller as the substituent
moves from the para to the ortho position. So too does the ratio
of the outer resonance to the inner resonance vary (becoming
smaller going toward the ortho position), indicating greater
0
1
′
′
′
′
′
′
2
3
4
5
6
119.3
138.4
18.3
119.3
138.8
18.3
119.0
139.0
18.3
25.7
25.9
25.8
Figure 2. Selected HMBC correlations for 5a used for the structural
assignment.
Magn. Reson. Chem. (2016)
Copyright © 2016 John Wiley & Sons, Ltd.
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K. Gopaul and N. A. Koorbanally
second-order coupling. This second-order coupling was brought
about by the substituents on ring B, wherein lone pairs were
involved in shielding H-10. The data in Table 1 indicate that this
effect is largest when the substituents are in the ortho position
The carbon resonances were in the expected aromatic region of
the spectrum and were assigned with the aid of the HSQC
spectrum. For C-1′, an HMBC correlation to H-10 was used to
confirm its assignment. The carbon resonances on the
acetophenone ring where the substituents occurred were easy to
identify because these carbon resonances had characteristic
chemical shifts; the fluorinated carbon resonances appeared as
doublets at ~δ 163; the chlorinated carbon resonances appeared
at ~δ 139 and the methoxylated carbon resonances appeared at
~δ 160. The fluorinated carbon resonances also had a large
characteristic J value of ~δ 250Hz, which made it easier to identify.
However, if one is not aware of the C―F coupling, these
resonances can be mistaken for impurities.
(
(
5b and 5h). The largest effect is seen with the chlorine atom
5e) (Fig. 3) (with the largest atomic radius) at C-2′, where the
interaction is so pronounced that H-9 and H-10 coalesce into a
1
singlet with the outer peaks being absent in the H NMR
spectrum.
In many instances, the resonances of either H-9 or H-10 are found
to overlap with the aromatic proton resonances, making it difficult
to distinguish. However, the resonances can be identified because
their coupling constants are known and one can identify these
peaks in an overlapping set of resonances. This is illustrated in
Fig. S1 (Supporting Information) where H-9 and H-10 are
completely separate resonances (5j), or when either H-10 (5g) or
H-9 (5k) occur in the multiplet along with the aromatic resonances.
The fluorinated compounds (5b–5d)
The resonances of the proton and carbon atoms of the quinoline
moiety remain unaffected by the fluoro group as it is located away
from the quinoline ring, and thus has no influence on its chemical
shift. However, the proton and carbon atoms on the acetophenone
ring and the ketoethylenic group are affected. The carbon
resonances of the B-ring are split into doublets because of C―F
coupling with J decreasing as the carbon moves further away.
These coupling constants may be used to identify the carbon
resonances of the B-ring as well as distinguish them from the
remaining carbon resonances of the molecule. Once identified,
these carbon resonances can then be used to identify their
corresponding proton resonances using the HSQC spectrum.
For compounds 5b–d (the fluorinated quinoline chalcones), the
C-2′ (ipso) carbon resonates far downfield because of inductive
effects by the fluorine atom. This resonance appears as a doublet
with a large coupling constant, which may be mistaken for two
separate carbon resonances. In 5b, the ortho carbons, C-1′ and
C-3′ resonate upfield at δ 126.8 (J = 13.1 Hz) and 116.7 (J= 22.9 Hz)
whilst the meta carbons, C-4′ and C-6′ resonate downfield at 134.3
(J = 8.8 Hz) and 130.7 (J= 6.2 Hz) respectively (Fig. S2). The
difference between the chemical shifts of these carbon atoms is
because of resonance effects of the fluorine atom. Even the
carbonyl carbon, which is three bonds away from the fluoro group,
is split into a doublet with a coupling constant of 2.3Hz. C-10 and
C-5′ resonate as doublets at δ 131.0 (J = 2.6Hz) and δ 124.6
(J = 3.4Hz) respectively (Fig. S2).
The acetophenone ring
In the absence of substituents on the B-ring, as in 5a, the H-2′/6′
resonance lies downfield in a multiplet with H-4 at δH 8.07–8.12
whilst H-3′/5′ and H-4′ are well resolved and resonate upfield at δH
7.51 and 7.60 respectively. For the para substituted compounds
5g, 5j, 5m and 5o, a pair of doublets for H-2′/6′ and H-3′/5′ are
observed because of ortho coupling as expected, with H-3′/5′
occurring more upfield than H-2′/6′ because of resonance effects
of the substituent. However, the H-3′/5′ resonance for compound
5d appears as a triplet rather than a doublet which is because of
splitting by both the neighbouring hydrogen and fluorine atoms.
When the phenyl ring is substituted at the meta position (5f, 5i,
5l and 5n), expected splitting patterns are observed for H-2′, H-4′
and H-5′. H-2′ resonates downfield as a meta coupled triplet, whilst
H-4′ resonates upfield as a doublet of doublets because of ortho
and meta coupling. H-5′ is split equally by the ortho protons, H-4′
and H-6′ and results in a triplet. For compound 5i, H-6′ resonates
downfield as a doublet of doublets as expected, however, this
splitting pattern is not observed in 5f and 5n. The meta coupling
between H-6′ and H-2′/4′ is not seen and H-6′ resonates as a
doublet. For compound 5l, the doublet of doublets for H-7 and
H-6′ overlap resulting in a multiplet.
For compounds 5e, 5h and 5k, the ortho substituted chalcones,
H-3′ and H-6′ are expected to be split into doublet of doublets with
one large (ortho) and one small (meta) J value and H-4′ and H-5′ into
triplets of doublets. This is the case for 5e but not for 5h and 5k.
Meta coupling for H-3′ and H-5′ is not observed in 5h and 5k. H-3′
resonates as a doublet and H-5′ as a triplet; however, H-4′
undergoes meta coupling and resonates as a triplet of doublets
because it is coupled to two ortho protons and a meta proton.
H-6′ resonates downfield as a doublet of doublets for 5k as
expected, but was unable to be resolved for 5h as it overlaps with
other resonances.
Although some of the resonances coalesce in 5b, it is possible to
identify the ortho coupling between H-4′ and H-3′ (J = 7.2Hz), H-4′
and H-5′ (J = 7.2 Hz), the meta coupling between H-4′ and the
fluorine at C-2′ (J = 5.1Hz) and with the proton H-6′ (J = 1.8 Hz).
The proton of the α,β unsaturated bond, H-10, four bonds away
from fluorine, was also split into a dd at δ
(Fig. S3).
Interesting splitting patterns are observed in the H NMR spectra
H
7.89 (J = 15.8, 2.6 Hz)
1
1
for the fluorinated compounds. For example, in the H NMR spec-
trum of 5b, second order coupling and H-F splitting can be seen
for H-10 and H-F splitting can be seen for H-3′-6′ (Fig. S3). For com-
pound 5b, H-4′ resonates as a dddd initially split by H-3′ and H-5′
with the same J value (7.2Hz) resulting in a triplet (actually a dd),
which is further split into a td (actually a ddd) by F (5.1 Hz) and then
into a dddd by H-6′ (1.8Hz) (Fig. S4). A similar pattern occurs with
H-5′ of compound 5c, which resonates as a ddd, split initially by
H-4′ and H-6′ (J = 8.0Hz) resulting in a triplet (actually a dd), which
is split further into a td (actually a ddd) by the meta fluorine atom
(5.7Hz) (Fig. S4).
Figure 3. The structure of 5e showing the interaction of H-10 with the
2-chloro substituent.
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Copyright © 2016 John Wiley & Sons, Ltd.
Magn. Reson. Chem. (2016)

Synthesis and structure elucidation of a series of chloroquinoline-2-chalcones
[
2] C.-H. Tseng, Y.-L. Chen, C.-Y. Hsu, T.-C. Chen, C.-M. Cheng, H.-C. Tso,
Single Crystal X-ray Diffraction Analysis
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D. Martin. Bioorg. Med. Chem. Lett. 2014, 24, 2046–2052.
[
A crystal structure of 5k (2-O-prenylated derivative) was solved in
the orthorhombic space group Pna2 , with one molecule in the
1
asymmetric unit. H-9 and H-10 are antiperiplanar with a dihedral
angle of 178.0°, which is consistent with the large coupling constant
[4] Y. R. Prasad, A. S. Rao, S. Sridhar, R. Rambabu. Int. J. Chem. Sci. 2008, 6,
34–244.
5] G. M. Sheldrick. Acta Crystallogr. Sect. A: Found. Crystallogr. 2008, 64,
12–122.
6] L. J. Farrugia, J. Appl. Crystallogr. 1999, 32, 837–838.
2
[
[
(J= 15.6 Hz) between H-9 and H-10. The core skeleton of 5k is
1
planar with the prenyl group lying out of the plane. The crystal
structure of compound 5k confirms that the molecule is in the E
configuration. An ORTEP diagram of 5k is provided in Fig. S5.
[7] S. S. Pawar, N. A. Koorbanally. Magn. Reson. Chem. 2014, 52, 279–288.
Supporting Information
Acknowledgements
Kaalin Gopaul thanks the National Research Foundation (NRF),
South Africa for a doctoral fellowship.
Additional supporting information may be found in the online ver-
sion of this article at the publisher’s web site.
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Magn. Reson. Chem. (2016)
Copyright © 2016 John Wiley & Sons, Ltd.
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