A novel and efficient synthesis of 3-aryl-5-(2-hydroxybenzoyl)pyridin-2(1H)-ones by re-cyclization of N-(oxopyranochromenyl)acetamides and their antineoplastic screening

Article abstract of DOI:10.1007/s11696-018-0566-8

Abstract: We have developed a novel, simple and efficient methodology for preparation of yet unknown 3-aryl-5-(2-hydroxybenzoyl)pyridin-2(1H)-ones 3(a–g) by EtONa driven re-cyclization of N-(3-aryl-2-oxo-2,5-dihydropyrano[3,2-c]chromen-5-yl)acetamides 2(a

Full text of DOI:10.1007/s11696-018-0566-8

Chemical Papers
https://doi.org/10.1007/s11696-018-0566-8
ORIGINAL PAPER
A novel and efcient synthesis of 3‑aryl‑5‑(2‑hydroxybenzoyl)
pyridin‑2(1H)‑ones by re‑cyclization of N‑(oxopyranochromenyl)
acetamides and their antineoplastic screening
Margita Lácová1 · Matúš Čakurda1 · Pavol Koiš1 · Gabriela Addová2 · Andrej Boháč1,3
Received: 12 May 2018 / Accepted: 31 July 2018
© Institute of Chemistry, Slovak Academy of Sciences 2018
Abstract
We have developed a novel, simple and efcient methodology for preparation of yet unknown 3-aryl-5-(2-hydroxyben-
zoyl)pyridin-2(1H)-ones 3(a–g) by EtONa driven re-cyclization of N-(3-aryl-2-oxo-2,5-dihydropyrano[3,2-c]chromen-
5-yl)acetamides 2(a–g) in good yields (80–95%). A mechanism for this reaction was proposed. The 3-aryl-2-oxo-2,5-
dihydropyrano[3,2-c]chromen-5-yl acetates 1(a–g) were prepared by cyclocondensation from 3-formylchromones
(4-oxo-4H-chromene-3-carbaldehydes) and acetic acids in 64–86% yields. Acetamides 2(a–g) were obtained by reaction of
3-aryl-2-oxo-2,5-dihydropyrano[3,2-c]chromen-5-yl acetates 1(a–g) with AcNH2 catalyzed by pTsOH in 80–93% yields.
Click chemistry precursors 4(a,d) and 5(a,d) were prepared by propargylation of 3(a,d) in 92–98% yields. They can serve
for construction of more complex molecules possessing pyridone skeleton of 3. Eleventh novel compounds 3(a–g), 4(a,d)
and 5(a,d) were screened on their anticancer activity on a panel of human tumour cell lines by NCI USA. We found that
pyridones 3–5 selectively inhibit the growth of some of the tumour cell lines at 10−5 M (up to -33% compared to a control).
The most sensitive tumour cell lines originated from kidney, breast, skin, ovary, blood and lung.
Graphical Abstract
Electronic supplementary material The online version of this
article (https://doi.org/10.1007/s11696-018-0566-8) contains
supplementary material, which is available to authorized users.
Extended author information available on the last page of the article
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Chemical Papers
Keywords 3-aryl-5-(2-hydroxybenzoyl)pyridin-2(1H)-ones · N-(3-aryl-2-oxo-2,5-dihydropyrano[3,2-c]chromen-5-yl)
acetamides · re-cyclization mechanism · NCI tumour cell lines · Click chemistry precursors
After a reaction of chromenecarbaldehydes ML-5 with
Introduction
amide derivatives ML-6 in the presence of TMSC pyridones
ML-7 were prepared in good yields. This type of reaction
performs with both primary and secondary amides having
an acidic methylene group in an alpha position in ML-6
(Ryabukhin et al. 2004) (Scheme 3). Similar reactions are
described also elsewhere (Bari et al. 2014), (Sengupta et al.
2012) and (Nohara et al. 1974).
Known 5‑(2‑hydroxybenzoyl)pyridin‑2(1H)‑ones
According to the SciFinder database, there are 789 regis-
tered structures possessing skeleton ML-4 (Scheme 1).
None of these structures has an aryl or heteroaryl substitu-
ent at C-(3) on the pyridone ring as present in our novel
compounds 3–5. Except a registered structure with benzimi-
dazolyl group at C(3) [CAS: 785791-96-0] with no proper-
ties and synthesis published. Two other compounds similar
to 3 [CAS: 339076-12-9 ML-1 and 339076-09-4 ML-2]
(Scheme 2) (Lácova et al. 1999 and 2000) do not have a full
aromatic substituent at C(3) and were prepared by diferent
methodology as described for 3–5 (Scheme 9 and 11).
So far, several synthetic pathways were developed for the
preparation of compounds ML-4 difering by starting mate-
rials and nitrogen containing reactants (Scheme 2).
Other pyridones ML-10 were prepared from ML-8,
esters of malonic acid ML-9 and aliphatic or aromatic
amines (Bari et al. 2016), (Rajkumar et al. 2015); NH3(liq)
(Gosh et al. 2001) and ammonium acetate (Maezono et al.
2016) (Scheme 4). This methodology was also used by oth-
ers (Poudel et al. 2015), (Mehrparvar et al. 2014).
Pyridones ML-12 were prepared in good yields from
oxochromenylacrylates ML-11 and primary amines in the
presence of Et3N (or K2CO3) in refuxing MeOH (Zhang
Scheme 1 Synthesis of pyri-
dones ML-1 and ML-2
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et al. 2010 and 2013) (Scheme 5). This method has been
used also by others (Sarma et al. 2016) and (Lv et al. 2010).
Biological activity of 5‑(2‑hydroxybenzoyl)pyri‑
din‑2(1H)‑ones
Pyridones 3–5 are not known and their biological activity
was not yet investigated. Therefore, we found the most sig-
nifcant bioactivities of their analogues possessing ML-4
skeleton (Scheme 2). They are active against some gram-
negative bacteria strains: Escherichia coli, Salmonella typhi,
Pseudomonas aeruginosa. They also have antifungal proper-
ties against Candida albicans, Aspergillus niger and Asper-
gillus favus (Bari et al. 2014). Pyridones conjugated with
tacrine fragment ML-(13–15) are potent AChE inhibitors
(Chand et al. 2016) (Fig. 1).
Scheme 2 Synthesis of pyridones ML-4 from chromenecarbalde-
hydes ML-3
The antiproliferative activity of pyridones was inves-
tigated on cancer cell lines (A549, HeLa, QGY7701,
SGC7901, MDA-MB231, SW480). Fourteen compounds
ML-18(a,b, g, h, k) and ML-20(g–k, o, r–t) have had
an interesting antitumour properties (GI50: from 0.11 to
0.99 μM), some of them also on multiple tumour cell lines
(Lv et al. 2010) (Scheme 6).
The antineoplastic activity of other 5-(2-hydroxybenzoyl)
pyridine-2(1H)-ones
Scheme 3 Synthesis of pyridones ML-7 from chromenecarbalde-
hydes ML-5
Scheme 4 Synthesis of pyridones ML-10 from ML-8. The particular yields and conditions are described as follows a/(Rajkumar et al. 2015), b/
(Gosh et al. 2001), c/(Abdel-Rahman et al. 2005), d/(Bari et al. 2016)
Scheme 5 Synthesis of pyri-
dones ML-12 from ML-11 and
primary amines
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Scheme 6 Structures and
synthesis of pyridones ML-18
and ML-20
Fig. 2 Structures and antineoplastic activities of pyridones ML-21
and ML-22
Fig. 1 Structures and activities of AChE inhibitors ML-(13–15)
acetic acid (Lácová et al. 2010). We also described the prep-
aration of acetate 1e (Kováčiková et al. 2010) (Scheme 7).
ML-21 and ML-22 was investigated on fve human can-
cer cell lines (HepG2, Lovo, A549, HT, MDA-MB 231)
(Bari et al. 2016), (Fig. 2).
The biological activity of acetates 1
The synthesis and biological activity of presented com-
pounds 3–5 is not yet described in the literature. We have
developed a methodology for the synthesis of pyridones
3 and their analogues 4–5 starting from 3-aryl-2-oxo-2,5-
dihydropyrano[3,2-c]chromen-5-yl acetates 1.
We found that some pyranochromenyl acetates 1 have an
interesting antineoplastic activity (NCI-60 human tumour
cell lines screen 2018). The most active was a compound 1
(R: 8,9-diMe, Ar: Ph with NCI code NSC: 745523) (NCI
data 2018).This compound allowed an average cell mean
growth up to only 11% at 10−5 M compared to a control
In 2010, we published a synthesis of acetates 1(a–b) from
4-oxo-4H-chromen-3-carbaldehydes ML-13 and substituted
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Scheme 7 Synthesis of acetates 1(a–b,e). MWI means a reaction carried out under microwave irradiation
The aim of this work was to investigate the reactivity of
the 2H-pyran-2-one part of the acetamides 2 under basic
conditions, to confrm the structure of products 3 and to
screen novel compounds for their antineoplastic activities.
Results and discussion
We have found that 3-aryl-5-(2-hydroxybenzoyl)pyridin-
2(1H)-ones 3 are formed after treatment of acetamides
2 by EtONa in EtOH. The conversion of acetamides 2 to
pyridones 3 is not yet described in the literature (SciFinder
2018). To prove the versatility of the above methodology, a
series of seven pyranochromenyl acetates 1(a–g) was pre-
pared by the conditions described in Scheme 7. Obtained
yields of 1(a–g) are depicted in Scheme 9. Subsequently,
acetamides 2(a–g) were prepared from acetates 1(a–g)
according to the conditions described in Scheme 9. In the
end, the acetamides 2(a–g) were used to prepare pyridones
3(a–g) confrming that the method converting compounds
2 to 3 by EtONa in EtOH is general and efcient (80–95%)
(Scheme 9).
Scheme 8 Synthesis of acetamides 2 from acetates 1
(100%) (One dose NCI assay). In a concentration-dependent
screening, this compound has an average GI50 =436 nM and
the best result for a particular cell line was GI50 = 40 nM
(Melanoma: MDS-MB-435) (NCI Search for all data by
compound identifers 2018). Although the mechanism of
antitumour properties for this compound was not yet deter-
mined, based on a comparative analysis (The Compare
Analysis 2018) of its GI50 activity profle on tumour cell
lines, tubulins were proposed as a target for this acetate 1
(Kováčiková et al. 2010).
A re-cyclization mechanism for the conversion of aceta-
mides 2 to pyridones 3 was proposed. (Scheme 10).
Pyridones 3(a, d) were derivatized by propargyl bromide
to prepare 4(a, d) and 5(a, d) (Scheme 11) They can serve as
precursors for a synthesis of more complex pyridone com-
pounds, e.g., via a Click chemistry approach.
By examining the reactivity of pyranochromenyl acetates
1, we found an efcient method for their conversion to aceta-
mides 2 (Lácová et al. 2010) (Scheme 8).
The biological activity of acetamides 2
Results of NCI biological assay
Only one acetamide 2b (NSC: 747828) was screened on its
antineoplastic activity at NCI USA (Lácová et al. 2010).
This compound infuenced several tumour cell lines. The
best antineoplastic efect at 10−5 M (One-dose NCI assay)
was obtained on a cell line of leukaemia (RPMI-8226) where
2b reduced 45% of a cell growth compared to a control
(100%).
Eleven 5-(aroyl)-3-arylpyridin-2-ones 3(a–g), 4(a, d) and
5(a, d) were screened on 59 human tumour cell lines in the
NCI USA. These compounds have shown a mild antitumour
activity at 10−5 M concentration (One dose NCI assay). The
most active pyridone is 3d (NSC: 804246), which has been
shown to reduce the growth of some breast, ovarian and
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Scheme 9 The conversion of acetates 1 to acetamides 2 and further to pyridones 3
Scheme 10 The proposed mechanism for the re-cyclization of the acetamide 2a to the pyridone 3a by EtONa in EtOH
melanoma tumour cell lines from 25 to 32% compared to
a control. Other interesting pyridones are both N-propar-
gylated derivatives 4d and 5d (NSC 804248 and 804249)
having the best inhibitory activity on two types of kidney
tumour cell lines (UO-31 and CAKI-1) and slowing the
growth of these lines from 28 to 33% compared to the con-
trol (100%) (Table 1).
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Scheme 11 Derivatization of
pyridones 3(a,d) by propargyl
bromide under various condi-
tions performing mono- 4(a,d)
or disubstituted 5(a,d) propargyl
derivatives
or 600 MHz and 75 or 150 MHz, resp.), chemical shifts are
given in parts per million (ppm), tetramethylsilane was used
as an internal standard and DMSO-d6 as the solvent, unless
otherwise specifed. IR spectra were acquired on FT-IRATR
REACT IR 1000 (ASI Applied Systems) with diamond
probe and MTS detector. Mass spectra were performed on
LC–MS (Agilent Technologies 1200 Series equipped with
Mass spectrometer Agilent Technologies 6100 Quadrupole
LC–MS). The course of the reactions was followed by TLC
analysis (Merck Silica gel 60 F254). UV lamp (254 nm,
366 nm) and iodine vapours were used for the visualiza-
tion of TLC spots. Starting chemicals were purchased from
Sigma-Aldrich, Fluorochem, Alfa Aesar or Acros vendors.
Used abbreviations EA, Hexsol, FLC and TLC mean ethyl
acetate, a fraction of hexanes similar with polarity to petrol
ether, fash liquid chromatography and thin-layer chroma-
tography, resp. All novel compounds are characterized by
their M.p., NMR diagrams, NMR and IR textual solutions,
their spectra fgures and elemental analysis (see Supple-
mentary material). 1H-NMR diagrams allow smart check of
both chemical shifts and coupling constants for their com-
pleteness and correctness. The numbers in the diagrams
mean chemical shift in δ ppm and number(s) in parenthesis
represent(s) coupling constant(s) in Hz.
Conclusions
We have prepared and characterized 25 compounds 1–5,
of which only acetates 1(a–b,e) and acetamides 2(a-b) are
already published by us previously (Lácová et al. 2010).
Other 20 compounds 1–5 are novel. On seven derivatives,
we tested the methodology for synthesis of acetates 1(a–g)
as well as the efciency of their acetoxy group replacement
to produce the acetamides 2(a–g). We have developed a
novel, simple and convenient methodology for preparing the
previously unknown 3-aryl-5-(2-hydroxybenzoyl)pyridine-
2(1H)-ones 3(a–g) from acetamides 2(a–g). The mechanism
of acetamides 2 conversion to pyridones 3 was proposed.
Eleven pyridones 3(a–g), 4 (a,d) and 5(a,d) were screened
on their antineoplastic properties by the NCI in USA. We
have found that tested pyridones 3–5 selectively inhibit a
growth of some tumour cell lines up to −33% compared to
the control (100%). The results of antineoplastic screens on
59 types of human tumour cell lines are present in Table 1
and the data from NCI assays are present in the Supplemen-
tary material.
Experimental
Melting points were measured using a Kofer apparatus or
Barnstead Electrothermal IA9200 and are uncorrected. 1H-
and 13C-NMR spectra were recorded on Varian Gemini (300
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Table 1 The best results of eleven 5-(aroyl)-3-arylpyridin-2(1H)-ones 3(a-g), 4(a,d) and 5(a,d) screened on the panel of 59 human tumour cell
lines at 10−5M concentration (One-dose NCI assay)
No. The structure
NSCa
Meanb The most growth inhibited human
tumour cell linesc
802890 90 %
804243 96 %
802892 90 %
Renal: -21 % (UO-31)
NSCL: -20 % (HOP-92)
3a
Renal: -24 % (UO-31)
3b
3e
-17 % (CAKI-1)
Renal: -17 % (UO-31)
802893 95 %
804246 87 %
NSCL: -14 % (NCI-H226)
Renal: -12 % (UO-31)
3c
Breast: -32 % (T-47D)
Ovarian: -26 % (OVCAR-4)
Melanoma: -26 % (UACC-62)
-25 % (SK-MEL-5)
Renal: -21 % (UO-31)
-19 % (CAKI-1)
3d
804244 103 % Renal: -18 % (UO-31)
3f
-15 % (CAKI-1)
802894 94 %
802898 95 %
Melanoma: -19 % (UACC-257)
3g
4a
Breast: -24 % (T-47D)
Renal: -24 % (UO-31)
Leukaemia: -22 % (K-562)
802899 91 %
Breast: -25 % (T-47D)
Renal: -19 % (UO-31)
-18 % (CAKI-1)
5a
804248 97 %
804249 91 %
Renal: -31 % (UO-31)
-28 % (CAKI-1)
4d
5d
Renal: -33 % (CAKI-1)
-28 % (UO-31)
aNSC means a NCI screening code
bThe mean represents an average of growth % through all 59 human tumour cell lines at used compound concentration 10−5 M compared to
100% for untreated tumour cell lines. The used cell lines were from leukaemia, NSCL, colon, CNS, melanoma, ovarian, renal, prostate and
breast tumours
c% number represents a decrease of a growth in a particular human tumour cell line (abbreviated in parenthesis) compared to the control. The
numbers marked in bold are growth inhibitions above 25%. One-dose NCI USA mean graphs of each screened compound can be found in the
Supplementary material
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Chemical Papers
Synthesis of 3‑aryl‑2‑oxo‑2,5‑dihydropyrano[3,2‑c]chromen‑5‑yl acetates 1(a–g)
General procedure A
paper. As an example, representative spectral data set of the
substance 1c is also given here.
A mixture of 1.74 g (10.0 mmol, 1.00 mol eq) of 4-oxo-
4H-chromone-3-carbaldehyde together with 1.50 g
(11.0 mmol, 1.10 mol eq) 2-phenylacetic acid and 138 mg
(1.00 mmol, 0.10 mol eq) of K2CO3 (abs) was stirred in
15 mL of freshly distilled Ac2O at 70 °C for 2 h. After cool-
ing the reaction mixture to rt, the precipitated product 1a was
fltered of, washed with H2O (3×10 mL), Et2O (3×10 mL)
and dried under vacuum to yield 2.374 g (7.1 mmol, 71%)
of 1a.
3‑(4‑Methoxyphenyl)‑9‑nitro‑2‑oxo‑2,5‑dihydropyra
no[3,2‑c]chromen‑5‑yl acetate (1c)
Compound 1c was prepared according to the General pro-
cedure A. In this case, the reaction was performed at 70 °C
within 2 h to yield 64% of product 1c.
Novelty compound 1c is not yet described in the
literature.
Characterization of all novel compounds from 1(a–g) are
given in an electronic supplementary material (ESM) to this
M.p. 253 °C (dec).
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Chemical Papers
1H-NMR (300 MHz, DMSO-d6) δ 8.43 (d, 1H,
J(8,10) = 2.8 Hz, H–C(10)), 8.31(dd, 1H, J(7,8) = 9.1 Hz,
J(8,10)=2.8 Hz, H–C(8)), 7.95 (s, 1H, H–C(4)), 7.72 (dm,
2H, among others J(2A,3A)=8.9 Hz, H–CA(2)), 7.55 (s, 1H,
H–C(5)), 7.41 (d, 1H, J(7,8)=9.1 Hz, H–C(7)), 7.02 (dm,
2H, among others J(2A,3A)=8.9 Hz, H–CA(3)), 3.79 (s, 3H,
−OCH3), 2.03 (s, 3H, –OCOCH3).
General procedure B
A mixture of 334 mg (1.00 mmol, 1.00 mol eq) 2-oxo-
3-phenyl-2,5-dihydropyrano[3,2-c]chromen-5-yl acetate
(1a) together with 59.0 mg (1.00 mmol, 1.00 mol eq) AcNH2
and 19.0 mg (0.10 mmol, 0.10 mol eq) pTsOH was stirred
in 7 mL of MeNO2at 70 °C for 2 h. After cooling the reac-
tion mixture to rt, a precipitated product was fltered of,
washed with MeNO2 (4 mL), Et2O (2 × 5 mL) and dried
under vacuum yielding 293 mg (0.88 mmol, 88%) of 2a.
Characterization of all novel compounds from 2(a-g) are
given in an electronic supplementary material (ESM) to this
paper. As an example, representative spectral data set of the
substance 2c is also given here.
13C-NMR (150 MHz, DMSO-d6) δ 169.3, 160.3, 159.4,
156.1, 148.4, 143.3, 137.4, 130.0, 127.9, 126.7, 126.6,
119.1, 118.6, 114.9, 114.3, 107.7, 90.0 C(5), 55.7 (–OCH3),
21.1 (–OCOCH3).
IR (neat, ν in cm−1): 2125 (w), 1988 (w), 1760 (m, C=O),
1733 (m), 1699 (s, C=O), 1653 (m), 1604 (m), 1582 (m),
1558 (m), 1527 (s, –NO2), 1488 (m), 1404 (m), 1371 (m),
1341 (s, –NO2), 1294 (m), 1254 (s), 1187 (s), 1127 (m),
1075 (m), 1038 (m), 1002 (s), 949 (s), 836 (s), 793 (m), 743
(s), 635 (m), 620 (m), 595 (m), 532 (m), 488 (m), 486 (m).
Anal. calcd for C21H15NO8 (409.35): C, 61.62; H, 3.69;
N, 3.42 Found: C, 61.87; H, 3.78; N, 3.52.
N‑(3‑(4‑methoxyphenyl)‑9‑nitro‑2‑oxo‑2,5‑dihydrop
yrano[3,2‑c]chromen‑5‑yl)acetamide (2c)
Compound 2c was prepared according to the General pro-
cedure B. In this case, the reaction was performed at 70 °C
within 2 h to yield 80% of product 2c.
Synthesis of 3‑aryl‑N‑(2‑oxo‑2,5‑dihydropy
rano[3,2‑c]chromen‑5‑yl)acetamides 2(a‑g)
and3‑aryl‑5‑(2‑hydroxybenzoyl)pyridin‑2(1H)‑ones
3(a‑g)
Novelty compound 2c is not yet described in the
literature.
M.p. 256.2–258.9 °C [MeNO2].
For structures, reaction conditions and yields see Scheme 9.
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1H-NMR (300 MHz, DMSO-d6) δ 9.34 (d, 1H,
J(HN,5) = 8.8 Hz, –HN–), 8.38 (d, 1H, J(8,10) = 2.8 Hz,
H–C(10)), 8.27 (dd, 1H, J(7,8)=9.1 Hz, J(8,10)=2.8 Hz,
H–C(8)), 7.79 (s, 1H, H–C(4)), 7.75 (dm, 2H, among others
J(2A,3A)=8.9 Hz, H–CA(2)), 7.29 (d, 1H, J(7,8)=9.1 Hz,
H–C(7)), 7.03 (dm, 2H, among others J(2A,3A) = 8.9 Hz,
H–CA(3)), 7.02 (d, 1H, J(HN,5)=8.8 Hz, H–C(5)), 3.81 (s,
3H, –OCH3), 1.86 (s, 3H, –HNCOCH3).
General procedure C
To a mixture of 200 mg (0.60 mmol, 1.00 mol eq) N-(2-
oxo-3-phenyl-2,5-dihydropyrano[3,2-c]chromen-5-yl)aceta-
mide (2a) in 5 mL of EtOH (abs), a solution of 81.0 mg
(1.35 mmol, 2.25 mol eq) of EtONa dissolved in 1.5 mL of
EtOH (abs) was added. The reaction mixture was stirred at
RT for 3 h. Then, 0.5 M HCl (aq solution) was added until
a product precipitation was observed. A light yellow solid
material was fltered of, washed with water, Et2O and dried
under vacuum to aford 160 mg (0.55 mmol, 91%) of 3a.
Characterization of novel compounds 3(a–g) are given in
an electronic supplementary material (ESM) to this paper.
As an example, representative spectral data set of the sub-
stance 3a is also given here.
13C-NMR (75 MHz, DMSO-d6) δ 169.5, 159.7, 159.1,
157.3, 147.3, 141.8, 137.2, 129.4, 127.2, 126.0, 125.9,
118.5, 117.4, 114.9, 113.7, 108.6, 75.8 C(5), 55.2 (–OCH3),
22.6 (–HNCOCH3).
IR (neat, ν in cm−1): 3448 (w), 3356 (m, -NH-), 3031 (w),
2966 (w), 2924 (w), 2835 (w), 2832 (w), 2322 (w), 2109
(w), 1996 (w), 1801 (w), 1727 (s, C=O), 1692 (s, C=O),
1648 (m), 1604 (m), 1577 (m), 1550 (m), 1508 (s, –NO2),
1479 (s), 1450 (m), 1396 (m), 1364 (m), 1332 (s, –NO2),
1292 (s), 1249 (s), 1233 (s), 1175 (s), 1096 (s), 1070 (s),
1030 (s), 942 (s), 917 (s), 895 (s), 876 (s), 837 (s), 790 (s),
756 (m), 739 (s), 683 (m), 634 (m), 606 (m), 569 (s), 546
(s), 528 (s), 484 (s), 452 (s).
5‑(2‑Hydroxybenzoyl)‑3‑phenylpyridin‑2(1H)‑one
(3a)
Compound 3a was prepared according to the General pro-
cedure C. In this case, the reaction was performed at RT
within 3 h to yield 91% of product 3a.
Anal. calcd for C21H16N2O7 (408.36): C, 61.77; H, 3.95;
N, 6.86 Found: C, 61.49; H, 3.71; N, 6.76.
Novelty compound 3a is not yet described in the
literature.
M.p. 214.4–216.7 °C [EtOH].
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1H-NMR (600 MHz, DMSO-d6) δ 12.28 (br s, 1H,
–HN–), 10.16 (s, 1H, –HO), 7.93 (d, 1H, J(4,6) = 2.5 Hz,
H–C(6)), 7.69 (d, 1H, J(4,6)=2.5 Hz, H–C(4)), 7.67 (dm,
2H, J(2B,3B) = 8.8 Hz, H–CB(2)), 7.41–7.32 (m, 5H, 2 x
H–CB(3), H–CB(4), H–CA(4), H–CA(6)), 6.96–6.91 (m, 2H,
H–CA(3) and H–CA(5)).
47.0 mg (0.343 mmol, 1.00 mol eq) K2CO3 in 6 mL of a
wet DMSO (or DMF) was stirred and cooled to 0 °C. A
solution of 49.0 mg (0.343 mmol, 1.00 mol eq) propargyl
bromide (80% solution in toluene) in 1 mL of DMSO (or
DMF) was added dropwise to the reaction mixture. After-
wards, the mixture was stirred 30 min at 0 °C and 2 h at
RT. Then, the reaction was diluted with 10 mL of water
and extracted with EA (3×5 mL), combined organic layer
washed with sat aq of NaCl (3×10 mL), water (10 mL) and
dried over Na2SO4. After fltration, the solution was concen-
trated by RVO, and obtained residue purifed by FLC (silica
gel, Hexsol/EA, 3/1) to yield 104 mg (0.316 mmol, 92%) of
5-(2-hydroxybenzoyl)-3-phenyl-1-(prop-2-yn-1-yl)pyridin-
2(1H)-one (4a) as a white solid compound.
13C-NMR (150 MHz, DMSO-d6) δ 192.0 (CCOC), 161.7,
155.8, 141.9, 136.8, 136.3, 132.9, 130.2, 129.9, 128.6,
128.5, 128.3, 125,6, 119.7, 117.4, 116.9.
IR (neat, ν in cm−1): 3086 (w, -NH-), 2995 (w), 2853 (w,
–OH), 2796 (w), 2738 (w), 2322 (w), 2277 (w), 2114 (w),
2087 (w), 1999 (w), 1652 (s, C=O), 1627 (s, C=O), 1591
(s), 1480 (s), 1446 (m), 1400 (m), 1331 (m), 1300 (m), 1281
(m), 1238 (s), 1219 (s), 1159 (m), 1140 (m), 1080 (m), 1026
(m), 979 (m), 949 (m), 906 (m), 877, 826 (m), 798 (s), 743
(s), 705 (s), 649 (s), 626 (s), 592 (s), 560 (s), 497 (m), 473
(m), 450 (m), 435 (m).
Characterization of novel compounds 4(a,d) are given in
an electronic supplementary material (ESM) to this paper.
As an example, representative spectral data set of the sub-
stance 4a is also given here.
Anal. calcd for C18H13NO3 (291.3): C, 74.22; H, 4.50;
N, 4.81 Found: C, 74.49; H, 4.22; N, 4.99.
5‑(2‑Hydroxybenzoyl)‑3‑phenyl‑1‑(prop‑2‑yn‑1‑yl)
pyridin‑2(1H)‑one (4a)
Synthesis of N‑propargyl derivative
of 3‑aryl‑5‑(2‑hydroxybenzoyl)pyridin‑2(1H)‑ones
4(a,d)
Compound 4a was prepared according to the General pro-
cedure D. In this case, the reaction was performed at 0 °C
within 3 h to yield 92% of product 4a.
For structures, reaction conditions and yields see Scheme 11.
Novelty compound 4a is not yet described in the
literature.
General procedure D
M.p. 130.7–132.9 °C [Hexsol/EA].
A solution of 100 mg (0.343 mmol, 1.00 mol eq)
5-(2-hydroxybenzoyl)-3-phenylpyridin-2(1H)-one (3a) and
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Chemical Papers
1H-NMR (300 MHz, CDCl3) δ 11.50 (s, 1H, –OH), 8.36
(d, 1H, J(4,6)=2.5 Hz, H–C(6)), 7.96 (d, 1H, J(4,6)=2.5 Hz,
H–C(4)), 7.70 (dm, 2H, J(2B,3B)=8.4 Hz, H–CB(2)), 7.66
(dd, 1H, J(5A,6A) = 8.1 Hz, J(4A,6A) = 1.7 Hz, H–CA(6)),
7.54 (ddd, 1H, J(3A,4A) = 8.3 Hz, J(4A,5A) = 7.3 Hz,
J(4A,6A) = 1.7 Hz, H–CA(4)), 7.47–7.35 (m, 3H,
2 × H–CB(3), H–CB(4)), 7.10 (dd, 1H, J(3A,4A) = 8.3 Hz,
J(3A,5A) = 1.2 Hz, H–CA(3)), 6.95 (ddd, 1H,
J(5A,6A) = 8.1 Hz, J(4A,5A) = 7.3 Hz, J(3A,5A) = 1.2 Hz,
H–CA(5)), 4.90 (d, 2H, J(CH,CH2)=2.6 Hz, –CH2−), 2.61
(t, 1H, J(CH, CH2)=2.6 Hz, –C≡CH).
94.0 mg (0.686 mmol, 2.00 mol eq) of K2CO3 in 8 mL of
wet DMSO (or DMF), a solution of 98.0 mg (0.686 mmol,
2.00 mol eq) of propargyl bromide (80% solution in toluene)
was added dropwise at 0 °C. Then, the reaction mixture was
stirred at RT for 2 h. After completion of the reaction (moni-
tored by TLC), 15 mL of water was added and resulting mix-
ture was extracted with EA (3×5 mL). Combined organic
layer was washed with sat solution of NaCl (3 × 10 mL),
water (10 mL) and dried over Na2SO4. After fltration, the
volatile parts were evaporated by RVO, and the residue puri-
fed by FLC (silica gel, Hexsol/EA, 5/1) to obtain 121 mg
(0.33 mmol, 96%) of 3-phenyl-1-(prop-2-yn-1-yl)-5-(2-
(prop-2-yn-1-yloxy)benzoyl)pyridin-2(1H)-one (5a) as a
white solid compound.
13C-NMR (150 MHz, CDCl3) δ 195.3 (CCOC), 162.6,
160.6, 140.3, 136.8, 136.3, 135.4, 131.7, 130.9, 128.6,
128.5, 128.3, 119.0, 118.82, 118.79, 117.4, 77.1, 76.0, 39.1
(-NCH-).
Characterization of novel compounds 5(a,d) are given in
an electronic supplementary material (ESM) to this paper.
As an example, representative spectral data set of the sub-
stance 5a is also given here.
IR (neat, ν in cm−1): 3293 (w, C–H), 3060 (w), 2922 (w,
–OH), 2324 (w), 2115 (w), 2098 (w), 1871 (w), 1741 (w),
1648 (s, C=O), 1603 (s, C=O), 1547 (m), 1483 (m), 1449
(m), 1416 (m), 1337 (m), 1265 (m), 1217 (s), 1158 (m),
1077 (m), 1029 (m), 991 (m), 967 (m), 913 (m), 860 (m),
822 (m), 788 (s), 757 (s), 696 (s), 671 (s), 621 (s), 562 (s),
528 (m), 467 (m), 434 (m).
3‑Phenyl‑1‑(prop‑2‑yn‑1‑yl)‑5‑(2‑(prop‑2‑yn‑1‑yl
oxy)benzoyl)pyridin‑2(1H)‑one (5a)
Anal. calcd for C21H15NO3 (329.35): C, 76.58; H, 4.59;
N, 4.25 Found: C, 76.37; H, 4.42; N, 4.60.
Compound 5a was prepared according to the General pro-
cedure E. In this case, the reaction was performed at RT
within 2 h to yield 96% of product 5a.
Synthesis of N,O‑bispropargyl derivative
of 3‑aryl‑5‑(2‑hydroxybenzoyl)pyridin‑2(1H)‑ones
5(a,d)
Novelty compound 5a is not yet described in the
literature.
M.p. 161.0–161.5 °C [Et2O/EA].
For structures, reaction conditions and yields see Scheme 11.
General procedure E
To a solution of 100 mg (0.343 mmol, 1.00 mol eq)
5-(2-hydroxybenzoyl)-3-phenylpyridin-2(1H)-one (3a) and
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Chemical Papers
1H-NMR (300 MHz, DMSO-d6) δ 8.31 (d, 1H,
J(4,6) = 2.5 Hz, H–C(6)), 7.84 (d, 1H, J(4,6) = 2.5 Hz,
H–C(4)), 7.64 (dm, 2H, among others J(2B,3B) = 8.8 Hz,
H–CB(2)), 7.55 (ddd, 1H, J(3A,4A) = 8.4 Hz,
J(4A,5A)=7.3 Hz, J(4A,6A)=1.6 Hz, H–CA(4)),7.44–7.32
(m, 4H, 2 × H–CB(3), H–CB(4), H–CA(3)) 7.26 (d, 1H,
J(5A,6A)=8.1 Hz, J(4A,6A)=1.6 Hz, H–CA(6)), 7.13 (ddd,
1H, J(5A,6A)=8.1 Hz, J(4A,5A)=7.3 Hz, J(3A,5A)=1.0 Hz,
H–CA(5)), 4.87 (d, 2H, J(CH, CH2)=2.4 Hz, –CH2−), 4.84
(d, 2H, J(CH, CH2) = 2.4 Hz, –CH2−), 3.50 (t, 1H, J(CH,
CH2)=2.4 Hz, –C≡CH), 3.45 (t, 1H, J(CH, CH2)=2.4 Hz,
–C≡CH).
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Afliations
Margita Lácová1 · Matúš Čakurda1 · Pavol Koiš1 · Gabriela Addová2 · Andrej Boháč1,3
2
* Andrej Boháč
Institute of Chemistry, Faculty of Natural Sciences,
andrej.bohac@fns.uniba.sk
Comenius University in Bratislava, Mlynská dolina,
Ilkovičova 6, 842 15 Bratislava, Slovakia
Matúš Čakurda
3
matus.cakurda@gmail.com
Biomagi, Ltd, Mamateyova 26, 851 04 Bratislava, Slovakia
1
Department of Organic Chemistry, Faculty of Natural
Sciences, Comenius University in Bratislava, Mlynská
dolina, Ilkovičova 6, 842 15 Bratislava, Slovakia
1 3