Synthesis of 3-cyano-2-pyridone derivative and its utility in the synthesis of some heterocyclic compounds with expecting antimicrobial activity

Article abstract of DOI:10.1002/jhet.4175

New 2-pyridone derivatives bearing p-methoxyphenyl and p-bromophenyl substituents at C-4 and C-6 were prepared smoothly by the one-pot reaction in high yield, and in a comparatively short time, it reacted with phosphorous oxychloride to produce the corresponding chloro compound. The latter was reacted with several nitrogen nucleophiles such as sodium azide, hydrazine, acetohydrazide, and benzohydrazide to give tetrazolo, hydrazino, and triazolo derivatives, respectively. The reaction of hydrazino derivative with cyclopentanone, furan-2-carbaldehyde afforded the corresponding hydrazone derivatives. Cyclocondensation of the latter compounds with thioglycolic acid afforded the nicotinamide derivatives. 2-Pyridone reacted with ethyl chloroacetate to afford chloroacetate and ethyl acetate derivatives. Ethyl acetate-derivative reacted with hydrazine hydrate and gave the acetohydrazide derivative, it was condensed with p-anisaldehyde and gave the 4-methoxybenzylidene acetohydrazide derivative. Also, 2-pyridone reacted with chloroacetic acid and or benzoyl chloride, afforded the benzoate derivative and 2-((6-(4-bromophenyl)-3-cyano-4-(4-methoxyphenyl) pyridin-2-yl) oxy) acetic acid, respectively. Structures of the products were confirmed using spectroscopic data and elemental analyses. Antibacterial activity of the synthesized compounds was evaluated against Escherichia coli and Staphylococcus aureus.

Full text of DOI:10.1002/jhet.4175

Synthesis of 3- cyano-2-pyridone derivative and its utility in the synthesis of some
heterocyclic compounds with expecting antimicrobial activity
Maher A. EL-Hashasha, Safaa S. Shabana*, Rania S. Alib
aHeterocyclic Synthetic Laboratory, Chemistry Department, Science Faculty, Ain Shams
University, Abbassia 11566, Cairo, Egypt.
b Department of basic science, Faculty of Industrial Education, Helwan University, Cairo, Egypt
11795 *Corresponding author: E- mail: safashaban@ymail.com
Abstract:
New 2-pyridone derivatives bearing p-methoxyphenyl and p-bromophenyl substituents at C-4 and C-6, were prepared
smoothly by the one‐pot reaction in high yield, and in a comparatively short time, it reacted with phosphorous oxychloride
to produce the corresponding chloro compound. The latter was reacted with several nitrogen nucleophiles such as sodium
azide, hydrazine, acetohydrazide, and benzohydrazide to give tetrazolo, hydrazino, and triazolo derivatives respectively.
The reaction of hydrazino derivative with cyclopentanone, furan-2-carbaldehyde afforded the corresponding hydrazone
derivatives. Cyclocondensation of the latter compounds with thioglycolic acid afforded the nicotinamide derivatives. 2-
Pyridone reacted with ethyl chloroacetate to afford chloroacetate and ethyl acetate derivatives. Ethyl acetate derivative
reacted with hydrazine hydrate and gave the acetohydrazide derivative, it was condensed with p-anisaldehyde and gave
the 4-methoxybenzylidene acetohydrazide derivative. Also, 2-pyridone reacted with chloroacetic acid and or benzoyl
chloride, afforded the benzoate derivative and 2-((6-(4-bromophenyl)-3-cyano-4-(4-methoxyphenyl) pyridin-2-yl) oxy)
acetic acid respectively. Structures of the products were confirmed using spectroscopic data and elemental analyses.
Antibacterial activity of the synthesized compounds was evaluated against E.coli and S. aureus.
.
Keywords: Chloropyridine, tetrazole, triazole, thiazolidine.
Introduction:
[1]
The pyridine nucleus exists in a lot of products like food, vitamins, plants, dyes, adhesives, pesticides, and drugs
.
Figure 1. It is oftentimes utilized in drugs because it capable of forming hydrogen bonds, solubility in water, and its
basicity. In recent years, various substituted heterocycles containing pyridine moiety have shown significant activity as
antibacterial[2], antiviral[3],anti-inflammatory agents[4], antihypertensive[4,5], analgesic[6], antipyretics[7], divretic[8],
antiasthmatic[9,10], antioxidant[11], antifungal[12], cardiovascular agents[13] , treatment of Alzheimer's disease[14]
, and
HIV-1 specific reverse transcriptase inhibitors[15].. It was worth mentioning that different pyridine and pyrazole were
noticed to have a significantly broad range of applications particularly as anticancer agents [16, 17]. The sake of the
current study is to construct a novel group of pyridine derivatives that might have biological activity as the continuation
of our efforts [18-24] conducted in the direction of preparation of novel heterocyclic compounds with expected biological
activity.
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Fig 1 structure of some pyridine drugs
Results and Discussion:
Condensation of 4-bromo acetophenone and 4-methoxy benzaldehyde (Claisen–Schmidt, base-catalyzed) afforded (1-
(4-bromophenyl)-3-(4-methoxyphenyl) prop-2-en-1-one (1). This procedure involves longer reaction time and lower
yield (yield: 68%, reaction time: 5 hours and m.p: 170–172 °C). [25] The reaction proceeds via the production of the
enone 1 accompanied by Michael's reaction through the addition of ethyl cyanoacetate, then cyclization to give the
desired pyridone 2 (route a). A particular kind of organic synthetic protocol characterized by mixing three reactants or
more, allowing them to interact together to yield the requested compound in a one-pot procedure is known as multi-
component reactions. Facile one‐pot, four‐component condensation of 4-methoxy benzaldehyde, 4-bromo
acetophenone, ethyl cyanoacetate, and ammonium acetate proceed smoothly [19], to afford new 2-pyridone derivative 2
(route b), in high yield and in a relatively short time (Scheme 1).
Scheme 1. One pot formation of 2- pyridone derivative 2 via multicomponent approach.
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The reaction proceeds via condensation of 4-methoxybenzaldehyde with the reactive CH2 group in ethyl
cyanoacetate, rather than the less active methyl group in 4-bromoacetophenone. Then the resulted cyanoacrylate
undergoes Michael addition with 4-bromo acetophenone, with subsequent substitution of enolic OH by NH2, then
cyclization with the removal of ethyl alcohol then dehydrogenation to give the desired product 2.
The chemical structure of pyridone 2 was proved by spectral data, since its infrared exhibited bands at 3267, 2221, and
1659 cm-1 for NH, CN, and CO groups, respectively. The 1 H-NMR spectrum showed singlet signals at δ 4.57 and 12.52
ppm, due to NH and OH proton, respectively. The above-mentioned spectroscopic data indicate the presence of lactam–
1
lactim dynamic equilibrium. From the intensity of the HNMR spectrum, the ratio of NH signals to OH signals was
(36:100) or ca (1:3). This means that the lactim form is more predominate in solution [21, 23] (Scheme 2).
Scheme 2. Lactam–lactim Tautomerism.
The latter compound was utilized as a start for the formation of diversified new heterocyclic products (Scheme 3), thus
pyridone derivative 2 reacted with phosphorous oxychloride , phosphorous pentachloride, and yield the chloro
compound[19] 3. The chemical structure of the chloro derivative 3 was elucidated using its micro elemental analytical
and spectroscopic information. The infrared spectrum presented the disappearance of the NH, CO bands, along with the
1
appearance of strong, sharp bands at 2220, 650 cm–1 for CN and C–Cl aryl. H NMR spectrum displayed singlet,
multiplet peaks at 3.84 together with 7.16 – 8.23 ppm, for methyl and aromatic protons.
Scheme 3. Reaction of chloro derivative 3 with different nitrogen nucleophiles.
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The behavior of chloro derivative 3 towards different nitrogen nucleophiles has been investigated with the aim to get
new heterocyclic compounds. Chloro compound 3 reacted with sodium azide and gave the corresponding tetrazolo
derivative [20, 26] 4. Tetrazolo derivative 4 was proved from the infrared spectrum which presents bands at 2220, 1100
cm–1 for CN, tetrazole ring mode. As well, MS clarifies a peak due to its molecular weight. The reaction of hydrazine
hydrate and chloro derivative 3, afforded hydrazino derivative 5. The infrared spectrum of the hydrazino derivative 5
exhibited strong bands at 3430, 3343 cm-1 for NH2, and NH. 1H NMR spectrum offered singlet signals at 4.62 together
with 9.51 ppm due to NH2 and NH protons, respectively (D2O exchangeable). The reaction of acetic anhydride with
hydrazino derivative 5 afforded the pyrazole derivative 6, and not the expected triazole derivative 7. Here authors offer
speculation that the addition of NH2 moiety of hydrazino derivative on the cyano group takes place easier than acylation
followed by cyclization to produce the triazolo derivative 7. This was proved by spectroscopic information, where the
infrared data of pyrazole derivative 6 was devoid of any absorption concerning to cyano group and revealed strong
1
absorption bands at 3435, 1729 cm-1 due to NH, CO groups respectively. H NMR spectrum presents three singlet
signals at 2.16, 3.85 in addition to 10.84 ppm assigned to 2 (NCOCH3), OCH3 plus NH protons.
It was worth mentioning that treatment of the chloro compound 3 with acetohydrazide and/or benzohydrazide in
refluxing n-butanol afforded the triazolo derivatives 7a-b [27] (Scheme 4).
Scheme 4. Suggested mechanism for the formation of 7a–b.
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The infrared and 1H NMR spectra of 7a, 7b were void of any signal related to the proton of the NH group. Treatment of
the hydrazino derivative 5 with cyclopentanone and/or furan-2-carbaldehyde in refluxing DMF and drops of acetic acid
yielded the pyridine derivatives [27] 8a and 8b, respectively. Compounds 8a, 8b got support from their spectroscopic
information, where the infrared spectra were devoid of any absorption bands for the CN group, and exhibited strong
absorption bands around 3197, 3146, 1657, and 1663 cm-1 attributed to NH2 and carbonyl of amide. (The amide moiety
1
produced from acid hydrolysis of the nitrile group). H NMR spectra showed singlet signals near δ 8.98–9.20 besides
11.52–11.80 ppm, for NH2 amide along with NH, (D2O exchangeable). The reaction between compounds 8a, 8b and
thioglycolic acid [27] takes place via thia Micheal addition (cyclocondensation) and gave spiro, thiazolidine derivatives
9a and 9b, respectively (Scheme 5).
The infrared spectra of nicotinamide derivatives 9a, 9b displayed absorption bands at 3205, 1665, 1671, 1673, and
1637 cm–1 assigned to NH and carbonyl group.
Scheme 5. Formation of derivatives 8a- b and 9a-b.
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Pyridine chloroacetate derivative 10 was obtained by refluxing dihydropyridine 2, ethyl chloroacetate together with
sodium ethoxide in absolute ethanol. The infrared spectrum of compound 10 presented a band near 1750 cm-1 accounts
for CO (chloroester). While pyridine derivative 11 was obtained when the reaction was carried out in dry acetone plus
anhydrous potassium carbonate. The infrared spectrum of acetate derivative 11 displayed a strong absorption band near
1733 cm-1 attributed to the carbonyl of ester. The 1H NMR spectrum displayed signals near 4.24, 1.12, along with 5.04
ppm as a quartet, triplet, and singlet, respectively for (CH2CH3) and (CH2CO) protons (Scheme 6). Whereas the
reaction of acetate derivative 11, hydrazine hydrate gave the corresponding acetohydrazide 12. The infrared spectrum of
1
12 detected bands at 3439, 3341 as well as 1644 cm‒1 for NH2, NH and carbonyl groups, respectively. Whilst its H -
NMR presented two broad singlet signals near 9.01 - 9.21 together with 9.50 ppm assigned to NH2 and NH protons.
Moreover, acetohydrazide 12 was reacted with p- anisaldehyde and gave the corresponding benzylidene derivative 13.
infrared spectrum of 13 display absorption bands near 3062 , 2221,1660 besides 1620 for NH, CN, CO in addition to
C=N groups, respectively.
Benzoate derivative 14 was achieved by refluxing dihydropyridine 2 together with benzoyl chloride in boiling pyridine.
The infrared spectrum of the benzoate derivative 14 did not present any signal for NH but gave a signal for C=O near
1761 cm-1. Analogously, pyridine acetic acid derivative 15 was prepared by refluxing dihydropyridine 2 with
chloroacetic acid, fused sodium acetate in absolute ethanol [28]. This compound was produced via the O-alkylation
reaction for the hydroxyl group of compound 2, using chloroacetic acid as an alkylating agent. The infrared spectrum of
derivative 15 evidenced strong absorption bands near 3437, 1715 cm -1 for hydroxyl plus carbonyl groups, respectively.
Its 1 H NMR spectrum did not offer any signal due to the NH proton but showed a singlet signal near12.48 ppm for OH
proton (D2O exchangeable).
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Scheme 6. Formation of compounds 10 – 15.
The Antimicrobial activity of some prepared derivatives has been evaluated [29, 30]. The results obtained are tabulated in
Table 1.
Table 1: The Response of various types of the tested microorganisms to some of the prepared derivatives in vitro
culture
Escherichia Coli
Staphylococcus aureus
Gm(-) bacteria
Gm(+) bacteria
inhibition
zone
diameter
(mm)
inhibition
zone
diameter
(mm)
No.
Compound
% Activity index
% Activity index
1
2
2
3
12
12
48.0
48.0
13
52.0
56.0
14
18
16
18
10
3
4
4
21
16
18
NE
12
22
84.0
64.0
72.0
0.00
48.0
88.0
00.0
00.0
00.0
32.0
72.0
64.0
72.0
40.0
56.0
80.0
00.0
48.0
32.0
40
5
5
6
6
8a
8b
9a
11
12
13
14
7
14
20
8
9
NE
NE
NE
8
NE
12
8
10
11
12
10
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13
15
18
25
72.0
100
19
25
76.0
100
Cefoxitin
NE → Not Effective
The results of the antibacterial screening as listed in Table (1) indicate that derivatives 4, 5, 6, 9a, 15 showed the largest
activities against Gram negative bacteria Escherichia Coli, (derivative 9a has the maximum activity), and compounds
2, 3, 8b showed moderate activities. While derivatives 14 showed weak activity. Derivatives 8a, 11, 12, 13 were
inactive compounds against Escherichia Coli. Derivatives 4, 5, 6, 9a, 15 exhibited intensive activities against Gram
positive bacteria (Staphylococcus aureus). Likewise (compound 9a has the highest activity), derivatives 2, 3, 8a, 8b, 12,
14 have moderate activities .While compound 13 showed weak activity. Derivative 11 was an inactive compound
against Staphylococcus aureus.
Experimental:
All melting points were determined on a Gallenkamp electric melting point device (Shimadzu, Japan) and uncorrected.
The IR spectra were carried out on a Pye Unicam SP-3-300 Infrared spectrophotometer, characterized as
Thermoscintific Nitolet is in Waltham, MA02451, USA, using potassium bromide disks. Proton NMR and 13C-NMR
spectra were recorded on 300 spectrophotometers (Rheinstetten, Germany), 300 and125 MHz, respectively. TMS as
internal standard, and in DMSO-d6 solvents. Chemical shifts are documented in ppm. All mass spectra were done at 70
eV, carried out on Shimadzu GCMS-QP1000EX mass Spectrophotometer (Shimadzu Corp., Kyoto, Japan). All the
spectroscopic measurements were done at the NMR laboratory at the Faculty of Pharmacy; the Chemical Laboratories
Ministry of Defense, Egypt, the Microanalytical CHN data were run at, and Ain Shams University, Egypt (the Micro
Analytical Center). All the chemical reactions were monitored by TLC on silica gel coated aluminum sheets (Silica Gel
60 F254, Merck, and Kenilworth, NJ).
6-(4-Bromophenyl)-4-(4-methoxyphenyl)-2-oxo-1, 2-dihydropyridine-3-carbonitrile (2)
A multicomponent reaction, containing (1.99 g , 0.01 mol) of 4-bromo acetophenone , (1.37g , 0.01 mol ) 4- methoxy
benzaldehyde, ethyl cyanoacetate ( 1.13g , 0.01 mol ) ,and ammonium acetate ( 0.06 mol ) in absolute ethanol (40 mL)
was refluxed as a one-pot reaction for 20 min. The separated solid while hot was filtered, dried, and recrystallized from
0
1
methanol, Yellow crystals, yield 89%, m.p 281-283 C. IR (cm‒1) ν: 3267, 2221, 1659 (NH, CN, CO). H-NMR
(DMSO-d6), δ (ppm): 3.37 (s, 3H, OCH3); 4.57 (br.s, 1H, NH, D2O exchangeable), 6. 80 (d ,2H,ortho -OCH3) ; 7.53-
7.82 (m,5H, Ar-H + pyridine H5 ) ; 8.17 (d,2H ,ortho bromophenyl moiety) ; 12.52 (br.s,1H,OH , exchangeable with
D2O). 13C-NMR (DMSO): 54.97, 114.08(2), 105.98, 115.01, 116.81, 120.29, 121.73, 128.67(2), 130.95(2), 132.03(2),
139.19, 150.60, 155.51, 157.46, 160.98. MS m/z (%):380,[M-1].+(19);381, [M].+,(23), 364(32),338 (100),342 (12)
,156(43),158(7),111(13), 75 (56). Anal. Calcd for C19H13BrN2O2 (381): C, 59.86; H, 3.44; Br, 20.96; N, 7.35; Found: C,
60.00; H, 3.27; Br, 21.06; N, 7.19%.
6-(4-Bromophenyl)-2-chloro-4-(4-methoxyphenyl) nicotinonitrile (3)
Dihydropyridine 2 (3.81 g, 0.01 mol), PCl5 (2.08 g, 0.01 mol), and POCl3 (5 mL) were refluxed on a water bath for 4
h. Then the reaction mixture was cooled and poured gradually into crushed ice-cold water. The precipitate formed was
filtered off and recrystallized from methanol and gave 2-chloro-3-nicotinonitrile derivative 3 as Yellowish crystals,
0
1
yield 89 %, m.p 176-178 C. IR (cm‒1) ν: 2220, 650 (CN, C-Cl). H-NMR (CDCl3), δ (ppm) : 3.84 ( s ,3H , OCH3) ;
7.16 – 8.23 (m,9H, 8Ar-H + pyridine -H5 ) .13C-NMR (DMSO): 55.92,103.88,113.54(2),116.11,119.02, 121.54 ,127.33,
128.90(2), 131.0(2) ,131.09(2),137.82, 151.42,158.2,160,163.40. MS m/z (%):401, [M].+, Cl37, 30), 399, [M].+,Cl35,100)
365(44), 158(11), 156(34), 111(7), 75(50.8). Anal. Calcd for C19H12BrClN2O (400): C, 57.10; H, 3.03; Br, 19.99; Cl,
8.87; N, 7.01. Found: C, 57.23; H, 2.98; Br, 20.02; Cl, 8.79; N, 6.98%.
5-(4-Bromophenyl)-7-(4-methoxyphenyl) tetrazolo [1, 5-a] pyridine-8-carbonitrile (4)
A mixture of compound 3 (4 g; 0.01 mol) and NaN3 (0.65 g, 0.01 mol) in acetic acid (30 mL) refluxed for 5 h. ,cooled
then added to 200 mL cold water ,the formed precipitate was decanted, dried, and purified from dioxane, yield 76%,
m.p. 246–248 0C. IR (cm‒1) ν: 2220 (CN). 1H-NMR (DMSO-d6), δ (ppm): 3.79 (s, 3H,-OCH3), 7.12-8.37 (m, 9H, 8 Ar-
H + pyridine H 5). 13C-NMR (DMSO): 55.89, 103.4, 113.7(2), 116.2, 120.8, 121.1, 128.8(2), 129.2(2), 130.9 132(2),
134.8, 136.2, 152.4, 155.3, 160.8. MS m/z (%): 408 [M+2] .+ 5 ; 407 [M+1] .+ 8 ; 406 [M].+ 12, 375(4.2) ,380(1.1),349
(42), 244(33),193(100) ,154(43.5),137(26) ,117(23),78(48), 61(19).Anal. Calcd for C19H12BrN5O (406): C, 56.18; H,
2.98; N, 17.24. Found: C, 55.99; H, 3.00; N, 17.05%.
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6-(4-Bromophenyl)-2-hydrazinyl-4-(4-methoxyphenyl) nicotinonitrile (5)
A mixture of chloro derivative 3 (4 g, 0.01 mol) in ethanol (20 mL) , hydrazine hydrate (.0.64 mL,50-60% , 0.02 mol)
was heated under reflux for 7 h. , after cooling ,solid material was collected by filtration and recrystallized from (2:1)
DMF-dioxane, yellow crystals, yield: 79%, m.p. 189-1910C. IR (cm‒1) ν: 3430, 3343, 2205 (NH2, NH, CN).1H NMR
(DMSO- d6), δ (ppm): 3.84 (s, 3H, OCH3), 4.62 (br.s, 2H, NH2, D2O exchangeable), 7.22-8.23 (m, 9H, 8Ar-
H+pyridine-H5), 9.51 (br.s, 1H, NH, D2O exchangeable). 13C-NMR (DMSO): 54.87, 84.1, 114.8(2), 116.9, 119.2, 128.9
(2), 129.8(2), 131.1, 132.8(2), 137.8, 154.8 (2), 158.1, 159.4. MS m/z(%): 395 [M].+, 38.2 ; 379 (8.6),363(100),340(22),
308(3) ,229(11),186(10.7), 156(23), 75(48). Anal. Calcd for C19H15BrN4O (395): C, 57.74; H, 3.83; N, 14.17; Found,
57.86; H, 3.78; N, 14.10 %.
N-acetyl-N-(6-(4-bromophenyl)-4-(4-methoxyphenyl)-1H-pyrazolo [3, 4-b] pyridin-3-yl) acetamide (6):
A mixture of hydrazino derivative 5 of (3.95g, 0.01 mol), acetic anhydride (20 mL) was heated under reflux for 7 h. The
excess acetic anhydride and acetic acid were removed in vacuo, treated with crushed ice, the formed precipitate was
collected by filtration and purified from ethyl alcohol, yield 78%, m.p 259-260 0C. IR (cm‒1) ν: 3435, 1729 (NH, CO).
1H NMR (DMSO-d6), δ (ppm): 2.16 (s, 6H, –N (COCH3)2), 3.85 (s, 3H,-OCH3), 7.14-8.22(m, 9H, 8Ar-H+pyridine-
H5), 10.84 (br.s, 1H, NH). 13C-NMR (DMSO): 24.8(2),55.79, 90.2,114.8(2),121.2,128.5(2),129.8(2), 132.4(2),136,
,137.7,149.7, 150.4 153.9,154,154.7,158.8,172.2(2). MS m/z (%): 478[M-1].+, 8.7; 479[M].+, 12, 384(100), 363(34),
339(11.3), 325(7), 216(19),118(42), 75(51). Anal. Calcd for C23H19BrN4O3 (479): C, 57.63; H, 4.00; Br, 16.67; N,
11.69. Found: C, 57.80; H, 3.94; Br, 16.61; N, 11.72 %.
Triazolo derivatives 7 a, b
General method: A mixture of 2-chloro nicotinonitrile derivative 3 (4.79 g, 0.01 mol) in n -butanol (20 mL),
acetohydrazide, and or benzohydrazide (0.01 mol) was heated under reflux condition for 20 h., cooled. The separated
solid was recrystallized from the appropriate solvent to give compounds 7 a, b.
5-(4-Bromophenyl)-7-(4-methoxyphenyl)-3-methyl-[1, 2, 4] triazolo [4, 3-a] pyridine-8-carbonitrile (7a)
1
Dark -Yellow powder (dioxane), yield: 58%, m.p 221-223 0C. IR (cm‒1) ν: 2220 (CN). H NMR (DMSO-d6), δ (ppm):
2.41 (s, 3H,-CH3, triazole), 3.79 (s, 3H, OCH3), 7.22 - 8.74 (m, 9H, 8 Ar-H + pyridine – H5). 13C-NMR (DMSO):
12.2,55.54,103.7,114.8(2),116.9,121.2,126.8,128.9(2),,130.1(2),,132.7(2),,141.2,146.9,149.3,153.8,161,161.7.162.1.MS
.+
.+
+
m/z (%): 423 [M+4]
(4), 421 [M+2] .+,(32); 419 [M] (74) ; 404 [M-CH3] ,(100); 378(8), 332(9), 223(11),
158(7),78(48). Anal. Calcd for C21H15BrN4O (419): C, 60.16; H, 3.61; Br, 19.06; N, 13.36: Found: C, 60.30; H, 3.50;
Br, 19.00; N, 13.40%.
5-(4-Bromophenyl)-7-(4-methoxyphenyl)-3-phenyl-[1, 2, 4] triazolo [4, 3-a] pyridine-8-carbonitrile (7b)
Dark-yellow powder (DMF), yield 59%, m.p. 169-170 0C. IR (cm‒1) ν: 2220 (CN). 1H NMR (DMSO-d6), δ (ppm): 3.08
(s, 3H, OCH3), 6.84-8.36 (m, 14H, 13Ar-H+ pyridine -H5). 13C-NMR (DMSO): 54.9, 103.4,114.2(2),116.1,121.9,127.1
(2), 128.9(2),129.3(2),129.8(2),131.7,132.3(2),134.1,141.5,151.3,152.7,152.3,154.8,160.7,162.8 . MS m/z (%):483
[M+2].+,33;481[M].+ (71), 325(24),299(10), 225(7),156(9.1) ,75(52) Anal. Calcd for C26H17BrN4O (481): C, 64.88; H,
3.56; Br, 16.60; N, 11.64. Found: C, 65.05; H, 3.51; Br, 16.62; N, 11.56%.
Hydrazone derivatives 8 a, b
General method: A reaction mixture containing (3.95 g, 0.01 mol) of compound 5, (0.01mol) cyclopentanone, and or
furan-2-carbaldehyde in 25 mL DMF, drops of acetic acid was refluxed for 8 h. After concentration, the residues were
purified from ethanol to leave products 8a, b.
6-(4-Bromophenyl)-2-(2-cyclopentylidenehydrazinyl)-4-(4-methoxyphenyl) nicotinamide (8a):
Reddish-brown crystals (MeOH), Yield 74%, m.p 216–218°C. IR (cm‒1) ν: 3425, 3146, 1657, 1608(NH2, NH, CO,
C=N). 1H NMR (DMSO-d6), δ (ppm): 1.74 -2.08 (m, 8H, cyclopentylidene), 3.72 (s, 3H, OCH3), 7.07 - 8.22 (m, 9H, 8
Ar-H + pyridine – H5), 8.98 (br.s, 2H, NH2, amide), 11.52 (br.s, 1H, NH, D2O exchangeable). 13C-NMR (DMSO): 23.5
(2),29.4(2),55.86,109.1,111.3,114.2(2),121.4,128.6(2),129.3(2),132.1(2),133.7,138.2,150.1,153.2,160.8,163.2,167.8,
181.4 . MS m/z (%):479 [M+.], 25; 463(4.8), 435(100), 382(12), 184(18) 156(41), 75(62).Anal.Calcd for C24H23BrN4O2
(479): C, 60.13; H, 4.84; Br, 16.67 N, 11.69. Found, 60.28; H, 4.80; Br, 16.61; N, 11.7%.
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6-(4-Bromophenyl)-2-(2-(furan-2-ylmethylene) hydrazinyl)-4-(4-methoxyphenyl) nicotinamide (8b)
Off-white crystals (EtOH), yield 52%, m.p 204–206°C.IR (cm‒1) ν: 3423, 3197 1663, and 1615 (NH2, NH, CO amide,
1
C═N). H NMR (DMSO-d6), δ (ppm): 3.78 (s, 3H, OCH3), 6.59-6.72 (m, 2H, Furan ring), 7.18 – 8.14(m, 1H , furan
ring, 9H, 8 Ar-H + pyridine – H5), 8.21 (s, 1H, N=C-H), 9.20 (s ,2H,NH2 amide) ,11.80 (s, 1H, NH, D2O
exchangeable). 13C- NMR (DMSO): 54.94,109.4,111.3,112.8,114.2(2),118.7,121.3,128.2(2) , 130.1(2),131.7, 132.8(2),
134.2,136.8,138.3,144.8,148.6,151,153.8,160.8,164.6,168.9. MS m/z (%):491[M+.], 1.2.Anal. Calcd for C24H19BrN4O3
(491): C, 58.67; H, 3.90; Br, 16.26; N, 11.40.Found: C, 58.86; H, 3.78; Br, 16.20; N, 11.30%.
General method: (9a and b)
A mixture of derivatives 8a, or 8b (0.01 mol), thioglycolic acid (0.7 mL, 0.01 mol) in dry benzene (25 mL) was
refluxed for 10 hours. The solid obtained after evaporation of the solvent was filtered off and purified from the suitable
solvent to leave compounds 9a and b
6-(4-Bromophenyl)-4-(4-methoxyphenyl)-2-((3-oxo-1-thia-4- aza spiro [4.4] nonan-4-yl) amino) nicotinamide (9a)
Dark- yellow crystals (dioxane), Yield 69%, m.p 244-246 0C. IR (cm‒1) ν: 3208 (NH), 1665 (C=O), 1671 (C=O) cm–1.
1H NMR (DMSO-d6), δ, ppm: 1.76 (m, 4H, 2CH2 cyclopent), 2.04 (m, 4H, 2CH2 cyclopent), 2.98 (d, 2H, CH2S), 3.70
(s, 3H, OCH3), 7.38 (s, 2H, NH2, D2O exchangeable), 6.98 - 8.02 (m, 9H, 8Ar-H + pyridine- H5), 9.80 (s, 1H, NH, D2O
exchangeable).13C-NMR(DMSO):21.2(2),33.4,36.2(2),54.90,64.1,107.1,114.6(2),116.2,121.2,128.1(2),129.3(2),132.3
(2), 133.8,138.6,148.6,152.4,158.9,161.3,166.3,167.8 .MS m/z (%):553 [M+.], 32.Anal. Calcd for C26H25BrN4O3 S (553):
C, 56.42; H, 4.55; Br, 14.44; N, 10.12; S, 5.79. Found C, 56.55; H, 4.42; Br, 14.41; N, 10.14; S, 5.80%.
6-(4-Bromophenyl)-2-((2-(furan-2-yl)-4-oxothiazolidin-3-yl) amino)-4-(4-methoxyphenyl) nicotinamide (9b):
1
Dark yellow powder (dioxane), Yield 68%, m.p 302–304 °C. IR (cm‒1) ν: 3205 (NH), 1637 (C=O), 1673 (C=O).
H
NMR (DMSO-d6) δ 3.78(s,3H,OCH3), 4.20 (d, 2H, CH2-thiazolidine), 5.18 (s, 1H, thiazolidine), 6.52-6.64 (m, 2H,
Furan moiety), 7.02– 8.20 (m, 10H ,1H,furan moiety , 8 Ar-H , pyridine H-5), 8.02 (s, 2H, NH2 amide), 9.80 (br.s, 1H,
NH, D2O exchangeable.13C-NMR (DMSO): 32.7,54.90 ,64.4, 106.3,107.7 ,110.2, 114.9(2), 116.1, 120.4,
128.1(2), 129.4(2),132.8(2),133.6,138.1,142.1,147.3,150.8,153.2, 158.8,160.8,168.1,168.6.MS m/z (%):556
[M+.], 5.5 .Anal. Calcd for C26H21BrN4O4S (565): C, 55.23; H, 3.74; Br, 14.13; N, 9.91; S, 5.67. Found: C, 55.38; H,
3.68; Br, 14.15; N, 9.88; S, 5.72%.
6-(4-Bromophenyl)-3-cyano-4-(4-methoxyphenyl) pyridin-2-yl-2-chloroacetate (10)
A reaction mixture of dihydropyridine derivative 2 (3.81g, 0.01mol) and ethyl chloroacetate (4, 26 mL, 0.04 mol) in
absolute ethanol (15 mL) /sodium ethoxide (0.68 gm., 0.01mol) refluxed 6 hrs. After cooling, neutralization with dil-
HCl; the separated product was purified from benzene to afford 10. Yield 48%, yellow crystals, m.p. 288-290 0 C. IR
1
(cm‒1) ν: 2217, 1750 (CN, CO). H NMR (DMSO-d6), δ (ppm): 3.78(s, 3H,-OCH3), 4.54 (s, 2H, ClCH2CO-), 6.96-
8.02 (m, 9H, 8Ar-H + pyridine- H5).13C-NMR (DMSO): 41.2,54.9, 92.1,114.2(2),116.2,120.8,121.7,128.1(2),129.8(2),
131.2,132.1(2),138.6, 157.4,157.9,160.6,162.1,164.1. MS m/z (%):458[M+.], 65. Anal.Calcd for C21H14BrClN2O3 (458)
C, 55.11; H, 3.08; Br, 17.46; Cl, 7.75; N, 6.12. Found: C, 55.26; H, 3.02; Br, 17.42; Cl, 7.73; N, 6.06%.
Ethyl 2-((6-(4-bromophenyl)-3-cyano-4-(4-methoxyphenyl) pyridin-2-yl) oxy) acetate (11)
A mixture of dihydropyridine-3-carbonitrile 2 (3.81 g, 0.01 mol) / dry acetone (25 mL), ethyl chloroacetate (4.9 g, 0.04
mol), K2CO3 -anhydrous (5.5 g, 0.04 mol) was refluxed in a water bath for 12 hrs. After evaporation of the excess
solvent, the solid obtained was washed with H2O (to eliminate excess K2CO3), then purified from ethyl alcohol, yellow
1
crystals, yield 79%, m.p 166-1670C. IR (cm‒1) ν: 2223.1733 (CN, CO, ester). H NMR (DMSO-d6), δ (ppm): δ (ppm):
1.12(t, 3H, -CH2CH3 ester), 3.30 (s,3H,-OCH3),4.24 (q,2H,-CH2CH3ester),5.04 (s,2H,-OCH2CO) ,6.64-8.02 (m,9H,8Ar-
H+pyridineH5).13C-NMR(DMSO):14.8,55.9,60.8,62.9,90.8,110.2,114.1(2),116.1,120.2,128.3(2),129.4(2),131,132.6(2),
138.4,155.8,157.3,161.8,164.5,169.8.MSm/z(%):467[M].+(1),393(100),384(3),369(22),371(14) 156(34), 158(13),111(6)
75 (44).Anal. Calcd for C23H19BrN2O4 (467): C, 59.11; H, 4.10; Br, 17.10; N, 5.99. Found C, 59.23; H, 4.06; Br, 17.08;
N, 6.00%.
2-((6-(4-Bromophenyl)-3-cyano-4-(4-methoxyphenyl) pyridin-2-yl) oxy) acetohydrazide (12)
A mixture of acetate derivative 11 (4.67 g , 0.01 mol) in ethyl alcohol (35 mL) , hydrazine hydrate (1 mL, 0.02 mol,
98%) was boiled under refluxed for 7 hrs., the separated solid after cooling was filtered, purified using DMF, dark-
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0
yellow crystals, yield 72%, m.p 197-199 C. IR (cm‒1) ν: 3439 , 3341 ,2221, 1644 (NH2, NH, CN).1H NMR (DMSO-
d6), δ (ppm): 3.36 ( s ,3H , OCH3 ) ; 4.68 (s,2H, OCH2CO) ; 6.74-8.16 (m,9H, 8Ar-H + pyridine H5 ); 9. 01 - 9.21 (s,
2H, NH2); 9.50 (br.s, 1H, NH) with D2O exchangeable). 13C-NMR(DMSO):55.89,66.8,92.4,106.4,114.5(2),116.1,121.3,
.+
.+
41821,41621,(2)41926,(2),,4.121(2)4..24,4.821,4.824,4.726,48121,48.26,48624,MS m/z (%):453 [M] (5); 455 [M+2]
(2.3), 365(22),232(12), 156(33), ,158(14),109 (10.8),111(8.4),75(50). Anal. Calcd for C21H17BrN4O3 (453): C, 55.64; H,
3.78; Br, 17.63; N, 12.36. Found: C, 55.70; H, 3.73; Br, 17.59; N, 12.42%.
2-((6-(4-Bromophenyl)-3-cyano-4-(4-methoxyphenyl) pyridin-2-yl) oxy)-N'-(4-methoxybenzylidene)
acetohydrazide (13)
A mixture of the hydrazide derivative 12 (4.53 g, 0.01 mol), (1.36g, 0.01mol) p-methoxy benzaldehyde / DMF (30 mL)
was boiled under reflux 9 hrs. The precipitate formed was purified from ethanol to produce acetohydrazide derivative
13, orange needles crystals, yield 72%, m.p 181-183 0C. IR (cm‒1) ν: 3062, 2221, 1660 1620 (NH, CN, CO, C=N). 1H
NMR (DMSO-d6), the chemical) shift δ (ppm): 2.99 (s, 6H, 2 OCH3), 4.60 (s, 2H, OCH2CO), 6.76-7.73 (m, 13H, Ar-H
+ pyridine -H5), 8.60 (s, 1H, N=C-H), 11.20 (br.s,1H, NH,D2O exchangeable).13C-NMR(DMSO):54.89(2),66.4, 93.8,
114.4(2),114.8(2),116.1,121.9,128.8(2),129.2(2),130.4(2)131.6,132.2(2),138.8, 144.2,154.6, 159.8,162.2,
163.1,170.8. MS m/z (%):571 [M] .+ (3.8) , 388(14.6),335 (12.7), 156 (44),75 (38) .Anal. Calcd for C29H23BrN4O4
(571): C, 60.96; H, 4.06; Br, 13.98; N, 9.80. Found: C, 61.00; H, 3.94; Br, 14.00; N, 9.76%.
6-(4-Bromophenyl)-3-cyano-4-(4-methoxyphenyl) pyridin-2-yl benzoate (14)
A reaction mixture of 2-oxo-1, 2-dihydropyridine-3-carbonitrile derivative 2 (3.81 g, 0.01 mol), benzoyl chloride (1.4 g,
0.01 mol) / pyridine (25 mL) was refluxed 5 hrs. Then cooled, poured in cold water-crushed ice/dil- HCl, the precipitate
formed was purified from methanol, brown crystals, yield 64%, m.p 162-163 oC. IR (cm‒1) ν: 2222, 1761 (CN, CO) .1H
NMR (DMSO-d6): 3.79 (s, 3H, OCH3); 6.98 (d, 2H, ortho –OCH3),7.60-7.88(m, 8H, 7Ar-H + pyridine-H5),8,12(d,2H,
,ortho bromophenyl),8.20(d,2H,ortho benzoate).13C-NMR(DMSO):55.89,101.03,114.94(2),116.90,122.17(2),127.01,
129.33,130.28(2),131.96(2),134.81,139.78, 146.88, 158.52, 164.50,165.43. MS m/z (%):485[M].+(3.3) ,459(100),367
(18), 303(12),192(8),158(7), 75(52).Anal. Calcd for C26H17BrN2O3 (485): C, 64.34; H, 3.53; Br, 16.46; N, 5.77.Found:
C, 64.50; H, 3.50; Br, 16.42; N, 5.71%.
2-((6-(4-Bromophenyl)-3-cyano-4-(4-methoxyphenyl) pyridin-2-yl) oxy) acetic acid (15)
A mixture of 3- cyano-2-oxo-1, 2-dihydropyridine derivative 2 (3.81 g, 0.01mol), chloro acetic acid (0.94 g, 0.01 mol),
CH3COONa (0.82g, 0.01mol) /absolute ethyl alcohol (30 mL) was refluxed for 5 hrs. Then cooled, diluted with H2O for
removal of excess CH3COONa, acidified with dil-HCl to (pH=2.5). The solid formed was recrystallized from (EtOH),
1
yellow crystals; yield 82%, m.p. 290-2920C. IR (cm‒1) ν: 3437, 1715 (broad OH, CO acid). H NMR (DMSO-d6), δ
(ppm) : 3.80 (s, 3H , OCH3),3.98 (s,2H,OCH2CO), 6.91-8.10 (m,9H, 8Ar-H + pyridine H5 ); 12.48 ( s,1H,OH , D2O
exchangeable).13CNMR(DMSO):55.87,64.76,93.81,114.82(2),116.03,128.63(2),129,6(2),131.92(2),155.8,157.6,161.14,
164.9. MS m/z (%):438 [M-1].+(10),422(34),394(100),368(19), 214(7),158(29),75 (44). Anal. Calcd for C21H15BrN2O4
(439): C, 57.42; H, 3.44; Br, 18.19; N, 6.38. Found: C, 57.50; H, 3.38; Br, 18.20; N, 6.35%.
Antimicrobial activity:
The antibacterial screening was carried out at the Lab of Microbiology, Ain Shams University, Science Faculty, Cairo,
Egypt. The codes of the strains were Staph.aureus ATCC 6538 and E.coli ATCC25922.Compounds 2, 3,4,5,6, 8a, 8b,
9a, 11, 12, 13, 14 and 15 were examined in vitro for antibacterial activity against Staphylococcus aureus (Gram-
positive bacteria) and Escherichia coli (Gram-negative bacteria) by make use of disc diffusion technique [29, 30] at disc
concentration of 1 mg/mL. Cefoxitin was used as a standard antibacterial agent. DMSO was used as a solvent. The zone
of inhibition of bacterial growth rate was detected.
Conclusion:
This study introduces a facile, one-pot reaction for the synthesis of new 3- cyano-2-pyridione derivative and its
utility in the synthesis of new heterocyclic compounds. Some of the synthesized derivatives were checked against
Gram-negative bacteria (Escherichia Coli) and Gram-positive bacteria (Staphylococcus aureus). In general, these
compounds showed good to moderate antibacterial activity. Compound 9a possesses the maximum activity towards
Gram negative bacteria (Escherichia Coli), Gram positive bacteria (Staphylococcus aureus).
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Acknowledgment:
The authors would like to express their honest acknowledgment for chemistry department, faculty of science, Ain
Shams University.
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