Synthesis, 1H and 13C NMR assignment of novel 2-pyridone derivatives

Full text of DOI:10.1002/mrc.4321

Letter ‐ spectral assignment
Received: 27 May 2015
Revised: 19 July 2015
Accepted: 26 July 2015
Published online in Wiley Online Library: 14 September 2015
(wileyonlinelibrary.com) DOI 10.1002/mrc.4321
1
13
Synthesis, H and C NMR assignment of novel
2-pyridone derivatives
Karam Chand,a,b Atul K. Sharmaa and Sunil K. Sharmaa*
esterification of acrylyl acid derivatives of 4-oxo-4H-1-benzopyran
(9–11) with ethanol under acidic condition (Scheme 2). The methyl-
Introduction
The synthesis of the 2-pyridone core structure is an attractive target
for the synthetic organic chemist owing to its significance in medic-
inal chemistry.[1,2] In addition, 2-pyridone constitutes a structural
component of several naturally occurring lead compounds, such
as Huperzine A,[3] Fredericamycin A,[4] Camptothecin (CTP),[5]
Ilicicolin H, and Pyridoxatin.[6] Many drugs containing pyridone skel-
eton have been released into the clinical world and a few more are
under clinical trials, e.g. Amrinone,[7] Milrinone or Primacor[8] are
used as cardiotonic agents for the treatment of heart failure,
Perampanel[9] is used for the treatment of Parkinson’s disease,
Pirfenidone is used for the treatment of idiopathic pulmonary fibro-
sis, and Ciclopiroxolamine is used for the topical treatment of der-
mal infections.[10] The potential clinical applicability and
comparatively low toxicity of 2-pyridones have led the interest of
many researchers to explore the utility of this moiety for better
and varied pharmacological activities. Apart from the medicinal
properties, 2-pyridone derivatives serve as viable synthons to pyri-
dine, piperidine, quinolizidine, and indolizidine alkaloids and
pyridone-tethered systems for dyes and pigments.[11,12] Because
the substitution of various functional groups on pyridin-2(1H)-one
nucleus greatly affects the chemical shift values in the magnetic
resonance of the proton and carbon nucleus, herein, we have syn-
thesized a series of N-substituted derivatives of benzoylpyridin-
2-(1H)-ones and studied the impact of the different substituents
on the chemical shifts of the protons and carbons of pyridone ring
using one-dimensional (1D) and two-dimensional (2D) NMR spec-
troscopic techniques. This study may be helpful for the data explo-
ration and structural elucidation of newer naturally occurring and
synthetic 2-pyridone derivatives.
ation of the phenolic group for compounds 13 and 14 with methyl
iodide under basic conditions gave (E)-ethyl 3-(7/6-methoxy-4-oxo-
4H-chromen-3-yl) acrylates (15/16). All of the compounds were well
characterized from their physical and spectral data and by compar-
ing the data with literature value for the known compounds.
The desired 2-pyridone derivatives (17–34) were synthesized by
reacting (E)-ethyl-3-(4-oxo-4H-chromen-3-yl) acrylates (12–16) with
various alkylamines, or diaminoalkanes in the presence of
triethylamine. The reaction followed a two-step addition-elimination
sequence in one pot. First, the opening of chromone ring occurs by
the nucleophilic attack of the amine group followed by a rearrange-
ment leading to the formation of 2-pyridone ring (Scheme 2).
Experimental
The 1H and 13C NMR spectra were recorded either on Jeol-400
(400 MHz, 100.5 MHz) NMR spectrometer (JEOL USA, Inc.) or Bruker
Avance-300 (300 MHz, 75.5MHz) and Bruker Avance-400 (400 MHz,
100.5MHz) spectrometers (Bruker Corporation, USA) using CDCl3 as
solvent as well as an internal standard. The concentration of all sam-
ples was approximately 10–15 mg/0.5 ml of CDCl3 in 2.5-mm NMR
tube for spectral analysis, and the chemical shifts were referenced
1
to either the residual solvent peak (for H NMR) or the peak for
dutereated solvent (for 13C NMR). The NMR data were recorded at
296–299 K, with chemical shifts (δ) reported in parts per million
and coupling constants (J) in hertz. Signals are expressed as singlet
(s), doublet (d), triplet (t), quartet (q), multiplet (m), broad singlet (br
s), and broad multiplet (br m). The instrumental settings for the
Jeol-400 spectrometer were as follows: for the 1H spectrum, relaxa-
tion delay (RD) = 4.0 s, acquisition time (AQ) = 1.36 s, pulse
width = 11.57 μs, flip angle= 45°, digital resolution (DR) = 0.73 Hz,
and spectral width= 30 ppm. For the 13C spectrum, RD= 2 s,
AQ= 1.0s, pulse width = 11.75 μs, flip angle = 30°, DR= 0.95 Hz,
and spectral width = 314 ppm. The instrumental settings for Bruker
Avance-300 and Bruker Avance-400 spectrometers in proton NMR
were as follows: RD = 1.0s, AQ= 1.0 or 5.3 s; pulse width = 11.0 μs;
DR= 0.30Hz; spectral width= 19 or 20 ppm, and for 13C were as fol-
lows: RD= 2.0 s, AQ= 1.8s, pulse width= 8 μs, DR= 1.0 or 2.0 Hz,
Synthesis
A series of 32 pyridone derivatives described in this study were pre-
pared by following Schemes 1 and 2. The required key intermedi-
ates (12–16) were synthesized starting from corresponding
hydroxyacetophenone (1–3) by following the literature
method.[13,14] In the case of dihydroxyacetophenone (2–3), first
mono-acetylation was carried out using acetic-anhydride in basic
condition to give substrate 4–5 so as to avoid the formylation of
the benzene ring in the next step. 4-Oxo-4H-1-chromen-3-yl-
carbaldehydes (6–8) were then synthesized using Vilsmeir–Haack
formylation reaction. The formylation reaction was followed by
the Knoevenagel condensation with malonic acid to yield the re-
spective 4-oxo-4H-chromen-3-yl acrylic acid (9–11).The desired
pyridone precursors, i.e. compounds 12–14, were obtained by
*
Correspondence to: Sunil K. Sharma, Department of Chemistry, University of Delhi,
Delhi 110 007, India. E-mail: sksharma90@chemistry.du.ac.in
a Department of Chemistry, University of Delhi, Delhi 110007, India
b Centro de Quimica Estrutural, Instituto Superior Técnico, Universidade Técnica de
Lisboa, Av. RoviscoPais 1, 1049-001, Lisboa, Portugal
Magn. Reson. Chem. 2016, 54, 91–102
Copyright © 2016 John Wiley & Sons, Ltd.

K. Chand, A. K. Sharma and S. K. Sharma
Scheme 1. Synthesis of (E)-alkyl 3-(4-oxo-4H-chromen-3-yl)acrylate; reagents and conditions: (a) Ac2O, pyridine, 6 h; (b) POCl3, N,N-Dimethylformamide,
50 °C, 13 h; (c) CH2(COOH)2, pyridine, 1.5 h; (d) EtOH, conc. H2SO4 (2–3 drops), 12 h; (e) CH3I, K2CO3, anhyd. acetone, reflux, 12 h.
Scheme 2. Synthesis of pyridin-2(1H)-one derivatives; reagents and conditions: (a) R1NH2, NEt3, C2H5OH, reflux, 4–5 h.
and spectral width = 239 or 250 ppm. For 2D experiments, such as
COSY and HMQC, all data points (t2 × t1) were acquired with
2 K × 256 as per literature method.[15,16] In all 2D experiments, the
solvent resonance was suppressed by presaturation during the
relaxation delay. The high-resolution mass spectroscopy (HRMS)
was recorded on Agilent-6210 ES-TOF, JEOL JMX-SX-102A, and
Waters LCT Micromass-KC455. The organic solvents were dried
and distilled prior to their use. Reactions were monitored by
performing thin-layer chromatography (TLC) on silica coated
aluminium plates (Merck silica gel 60F254); the spots were visualized
either by UV light or by spraying with 5% alcoholic FeCl3 solution.
Silica gel (100–200 mesh) was used for column chromatography.
All of the chemicals and reagents were procured from Spectrochem
Pvt. Ltd., India and Sigma-Aldrich Chemicals Pvt. Ltd., USA. Melting
points were measured with a Buchi M-560 apparatus (BÜCHI
Labortechnik AG, Flawil, Switzerland) and are uncorrected.
(70 ml) was added triethylamine (2 drops), and the reaction mixture
was refluxed for 4–5 h. The progress of the reaction was monitored
on TLC. On completion of the reaction, the mixture was cooled to
room temperature, and the solvent was evaporated under reduced
pressure. The crude product was purified by column chromatogra-
phy over silica gel (100–200 mesh) in 20–40% ethyl acetate/
petroleum ether to give 2-pyridone derivatives (17–48) in
74–85% yield.
Results and discussion
All the compounds described in Scheme 2 were characterized from
their spectral data. The peak assignments in 1H and 13C NMR spec-
tra were carried by comparing the data with theoretical values ob-
tained from ChemDraw 10.0 (PerkinElmer, USA) as well the
literature reports. Also, additional experiments, e.g. COSY, HMQC,
and DEPT analysis were used for the peak assignment, the spectro-
scopic data are compiled in Tables 1–4. The constitution of com-
pounds was further confirmed by the HRMS data as summarized
in Table 5 along with their melting points. Analysis of the proton
NMR data (Tables 1 and 2) reveals that in all the N-substituted
benzoylpyridin-2-(1H)-one derivatives, H-6 of pyridone ring
General procedure for the synthesis of
N-substituted pyridone derivatives (17–48)
To a solution of (4-oxo-4H-chromen-3-yl) acrylate (12–13 & 15–16)
(4mmol) and aminoalkane/diaminoalkane (4.2mmol) in ethanol
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Copyright © 2016 John Wiley & Sons, Ltd.
Magn. Reson. Chem. 2016, 54, 91–102

Synthesis, 1H and 13C NMR assignment of novel 2-pyridone derivatives
Magn. Reson. Chem. 2016, 54, 91–102
Copyright © 2016 John Wiley & Sons, Ltd.
wileyonlinelibrary.com/journal/mrc

K. Chand, A. K. Sharma and S. K. Sharma
wileyonlinelibrary.com/journal/mrc
Copyright © 2016 John Wiley & Sons, Ltd.
Magn. Reson. Chem. 2016, 54, 91–102

Synthesis, 1H and 13C NMR assignment of novel 2-pyridone derivatives
appeared most deshielded either as a singlet or meta coupled dou-
blet in the range of 7.77–8.18 ppm due to the proximity of the asso-
ciated carbon with the electronegative nitrogen. While the
chemical shift value of H-4, which appeared as ortho coupled dou-
blet or ortho-meta coupled doublet of doublet, was found to be in
the lower frequency region (7.58–7.77 ppm) as compared with H-6.
The chemical shift value for this proton was further confirmed by
the COSY spectra (see Supporting Information). Furthermore, it
has been observed that H-3 exhibit a significant change in the
chemical shift value with the introduction/positional shift of the
functional group in the benzoyl ring. For 5-(2′-hydroxy-benzoyl)/
(2′-hydroxy-5′-methoxy-benzoyl)-1H-pyridin-2-one derivatives, H-3
appears in lower frequency region with respect to the aromatic
protons of benzoyl ring, however, in the case of 5-(2′,5′-dihydroxy-
benzoyl)/(2′-hydroxy-5′-methoxy-benzoyl)-1H-pyridin-2-ones, H-3
appeared at the higher frequency region in comparison to the
H-3′ and H-4′ of the benzoyl ring. Interestingly, the coupling con-
stant of the ortho coupled protons (H-3 and H-4) of 2-pyridone ring
was observed in the range of 9.3–9.5 Hz, whereas lower coupling
constant in the range of 7.5–8.8Hz was observed for the ortho
coupled protons of benzoyl ring; this information may be used to
distinguish the 2-pyridone ring’s protons from the benzoyl ring’s
protons, apart from the 2D (COSY) NMR analysis. The hydroxyl
group at the C-2′ of the benzoyl ring was observed to appear signif-
icantly deshielded (10.04–12.33 ppm) due to the chelation with the
neighboring carbonyl group(C-1′). The chemical shifts of all protons
of the alkyl chain are summarized in Table 2. The methylene group
linked to heterocyclic nitrogen (H-1″ and H-2″) appeared as a triplet
or multiplet in the high frequency region (3.91–5.28 ppm) and the
corresponding carbon (C-1″) was observed in the range
47–55ppm. The chemical shift values of the carbons of the
2-pyridone derivatives (17–48) are also summarized in Tables 3,
, 4. The presence of a characteristic peak in the range of
192–195 ppm in the proton noise decoupled 13C NMR spectra
of all the synthesized 2-pyridone derivatives confirms the link-
age of benzoyl ring to pyridone ring. The 1H–13C correlation spectra
reveals that C-6 appears slightly deshielded than that of C-4, i.e. the
C-6 and C-4 of 2-pyridone ring lies in the range of 139–145 and
137–139 ppm, respectively. The quaternary carbons, C-5 and C-1′
appeared in the range 115–118 and 110–119ppm, respectively.
The impact of the additional hydroxy/methoxy group or change
in the position of the functional group is clearly observed on
the chemical shift values of C-1′-C-6′ carbons of benzoyl ring
(Table 3). The chemical shift values of C-1′ of 5-(2-hydroxy-
benzoyl)-2-pyridones were observed in the range 118–120 ppm;
however, the introduction of the additional OH or OMe group
at C-4′ or C-5′ position of benzoyl ring led to a shift of C-1′ by
5–7 ppm towards the low frequency region. It has been observed
that the presence of a hydroxyl group at C-4′ results shielding of
C-3 of the 2-pyridone ring by 10–11 ppm, whereas introduction of
the methoxy group at C-4′ or C-5′ did not show any significant
change in the chemical shift in any of the 2-pyridone ring
carbons. Further, the N alkylation of 2-pyridone derivatives
showed no significant impact on the δ value of 2-pyridone or
benzoyl ring. The 1H-13C correlation spectra of the N,N-dialkyl
amino alkyl substituted pyridone derivatives showed that the
C-1″ carbon attached to the nitrogen of 2-pyridone ring appears
shielded in comparison to the carbon attached to the nitrogen
1
of alkyl amine. The H and 13C NMR chemical shift values of all
the remaining protons and carbons of 2-pyridone derivatives
were also assigned as shown in Tables 1–5 and confirmed by
1
1H–1H and H–13C correlation spectroscopy.
Magn. Reson. Chem. 2016, 54, 91–102
Copyright © 2016 John Wiley & Sons, Ltd.
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K. Chand, A. K. Sharma and S. K. Sharma
wileyonlinelibrary.com/journal/mrc
Copyright © 2016 John Wiley & Sons, Ltd.
Magn. Reson. Chem. 2016, 54, 91–102

Synthesis, 1H and 13C NMR assignment of novel 2-pyridone derivatives
Magn. Reson. Chem. 2016, 54, 91–102
Copyright © 2016 John Wiley & Sons, Ltd.
wileyonlinelibrary.com/journal/mrc

K. Chand, A. K. Sharma and S. K. Sharma
wileyonlinelibrary.com/journal/mrc
Copyright © 2016 John Wiley & Sons, Ltd.
Magn. Reson. Chem. 2016, 54, 91–102

Synthesis, 1H and 13C NMR assignment of novel 2-pyridone derivatives
Magn. Reson. Chem. 2016, 54, 91–102
Copyright © 2016 John Wiley & Sons, Ltd.
wileyonlinelibrary.com/journal/mrc

K. Chand, A. K. Sharma and S. K. Sharma
wileyonlinelibrary.com/journal/mrc
Copyright © 2016 John Wiley & Sons, Ltd.
Magn. Reson. Chem. 2016, 54, 91–102

Synthesis, 1H and 13C NMR assignment of novel 2-pyridone derivatives
Magn. Reson. Chem. 2016, 54, 91–102
Copyright © 2016 John Wiley & Sons, Ltd.
wileyonlinelibrary.com/journal/mrc

K. Chand, A. K. Sharma and S. K. Sharma
Table 5. High-resolution mass spectroscopy and melting point of all synthesized 2-pyridone derivatives
Molecular
formula
Mass (m/z)
calcd/found
Melting
point in °C
Molecular
formula
Mass (m/z)
calcd/found
Melting
point in °C
Compd.
Compd.
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
16H18N2O3 287.1396 [M + H]+ /287.1398
18H22N2O3 315.1709 [M + H]+ /315.1701
23H32N2O3 385.2491 [M + H]+ /385.2518
21H28N2O3 357.2178 [M + H]+ / 357.2173
146–148
73–75
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
C17H20N2O4 317.1496 [M + H]+ /317.1425
C19H24N2O4 367.1628 [M + Na]+ /367.1772
C24H34N2O4 415.2591 [M + H]+ /415.2588
C22H30N2O4 387.2278 [M + H]+ /387.2231
150–152
83–85
semi solid at rt
semi solid at rt
107–109
40–42
semi solid at rt
141–143
93–94
15H15NO3
16H17NO3
18H21NO3
18H19NO3
280.0944 [M + Na]+ /280.0949
272.1287 [M + H]+ / 272.1298
322.1419 [M + Na]+ /322.1418
298.1443 [M + H]+ / 298.1460
C16H17NO4
C17H19NO4
C19H23NO4
C19H21NO4
288.1236 [M + H]+ /288.1259
302.1387 [M + H]+ /302.1374
330.1700 [M + H]+ /330.1708
328.1543 [M + H]+ /328.1475
73–75
72–74
72–74
100–102
198–200
147–148
43–45
16H18N2O4 303.1367 [M + H]+ / 303.1372
18H22N2O4 353.1472 [M + Na]+ /353.1601
23H32N2O4 401.2435 [M + H]+ /401.2437
21H28N2O4 373.2127 [M + H]+ /373.2147
189–191
C17H20N2O4 317.1496 [M + H]+ /317.1435
C19H24N2O4 345.1809 [M + H]+ /345.1789
C24H34N2O4 437.2411[M + Na]+/437.2571
C22H30N2O4 387.2278 [M + H]+ /387.2278
160–162
184–187
74–76
semi solid at rt
201–203
33–35
15H15NO4
16H17NO4
18H21NO4
18H19NO4
296.0893 [M + Na]+ /296.0861
288.1236 [M + H]+ /288.1193
338.1368 [M + Na]+ /338.1378
336.1212 [M + Na]+ /336.1175
C16H17NO4
C17H19NO4
C19H23NO4
C17H21NO4
288.1230 [M + H]+ /288.1165
324.1206 [M + Na]+/324.1381
330.1705 [M + H]+ /330.1709
328.1543 [M + H]+ /328.1488
70–71
179–181
65–67
166–168
78–80
185–187
105–107
Conclusions
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Acknowledgements
The author K. C. is thankful to Erasmus NAMASTE consortium grant
(unique number: NAMASTE_20130125) for the award of postdoc-
toral fellowship. A. K. S. thanks the University Grants Commission
for the award of Junior and Senior Research Fellowships. Financial
support from the University of Delhi for the award of DST Purse
Grant 2 is gratefully acknowledged.
Supporting information
Additional supporting information may be found in the online ver-
sion of this article at publisher’s web site.
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