Short communication
A Rapid One-pot Synthesis of Pyrido[2,3-d]pyrimidine Derivatives Using Br0nsted-acidic Ionic Liquid as Catalyst
Roghayeh Hossein Nia,1 Manouchehr Mamaghani,1* Khalil Tabatabaeian,1
Farhad Shirini1 and Mehdi Rassa2
1 Department of Chemistry, Faculty of Sciences, University of Guilan, P.O. Box 41335-1914, Rasht, Iran
2 Department of Biology, Faculty of Sciences, University of Guilan, P.O. Box 41335-1914, Rasht, Iran
* Corresponding author: E-mail: m-chem41 @guilan.ac.ir and mchem41 @gmail.com
Fax: +98 1313233262
Received: 13-12-2012
Abstract
Pyrido[2,3-d]pyrimidine derivatives were synthesized regioselectivly in good to high yields by one-pot three-component condensation of 6-amino-2-(methylthio)pyrimidin-4(3ff)-one, aromatic aldehydes and ethylcyanoacetate or mel-drum's acid using 1,2-dimethyl-N-butanesulfonic acid imidazolium hydrogen sulfate ([DMBSI]HSO4) Br0nsted-acidic ionic liquid as catalyst. Solvent-free mild reaction conditions, short reaction times, easy work-up, and reusability of the catalyst are the main advantages of this protocol.
Keywords: 6-amino-2-(methylthio)pyrimidin-4(3ff)-one, ethylcyanoacetate, meldrum's acid, pyrido[2,3-d]pyrimidine, ionic liquid, one-pot three-component reaction.
1. Introduction
The medicinal value of pyrimidine derivatives is significant among various heterocycles and they are found to possess various biological activities.110 In particular, many pyrido[2,3-d]pyrimidine derivatives possess wide range of physiological properties, which include antibacterial,11 antiviral,12 diuretic, analgesic,13 anti-inflamma-tory,14 anticonvulsive,15,16 antipyretic,17 cardiotonic,18,19 antitumoral,7 bactericidal,20 antihistaminic,21 bronchiodi-lator22 and also act as a cyclin-dependent kinase 4 inhibitors.23 As a result, this class of compounds present considerable interest for research. The reactions of 6-amino thi-ouracil with precursors of a,0-unsaturated carbonyl com-
pounds are one of the most widely employed methods, as they allow synthesis of both pyrido[2,3-d]pyrimidines and their dihydro derivatives with different substituents in positions 5 and 7 of the heterocyclic system.24 The reaction between 6-aminouracils with cyano olefins,25 intramolecular hetero Diels-Alder reactions involving 1-oxa-1,3-butadienes26 and several others, have already been reported in the literature.27
On the other hand, ionic liquids have attracted an extensive interest as excellent alternatives to organic solvents, due to their favorable properties. The use of ionic liquids as reaction media may offer a convenient solution to both, the solvent emission, and catalytic recycling prob-lems.28,29 Recently, ionic liquids have been successfully
Scheme 1. Synthesis of [DMBSI]HSO4
employed as solvents with catalytic activity for a variety of reactions.30
These observations led us to attempt the synthesis of some pyrido[2,3-d]pyrimidine derivatives using 6-amino-2-(methylthio)pyrimidin-4(3H)-one in the presence of SO3H-functional Br0nsted-acidic halogen-free ionic liquid [DMBSI]HSO4 which bears a butanesulfo-nic acid group in 1,2-dimethyl-imidazolium cation as catalyst (Scheme 1).
2. Results and Discussion
As part of our program devoted to developing highly expedient, selective and environmentally friendly methodologies for the preparation of heterocyclic compounds,31 we describe here an efficient and rapid method for the re-gioselective synthesis of novel pyrido[2,3-d]pyrimidines, using ionic liquid as catalyst. Due to the formation of different condensation products, depending on the specific conditions, reactions of 6-amino-2-(methylthio)pyrimidin-4(3H)-one, aldehydes and CH-acid compounds have recently attracted the interest of many chemists.32 Although
most of these processes offer distinct advantages, they suffer from certain drawbacks such as high costs, longer reaction times, harsh reaction conditions, and the use of volatile organic solvents. Therefore, the possibility of performing reactions under solvent-free conditions with ionic liquids could enhance their efficiency from an economic as well as a green point of view.
In this report we have devised a rapid and convenient one-pot three-component reaction for the synthesis of annulated derivatives of pyrimidines (4a-h, 7a-e) (Schemes 2 and 3) .
In the initial experiments, the starting compound 1 was prepared by condensation of thiourea with ethylcya-noacetate in sodium ethoxide, and followed by alkylation with methyl iodide.33 Compound 1 was then used in a three-component reaction for the synthesis of 5-(4-chlorop-henyl)-3,4,7,8-tetrahydro-2-(methylthio)-4,7-dioxopyri-do[2,3-d]pyrimidine-6-carbonitrile (4d) as a model compound (Scheme 2). To optimize the reaction conditions, different solvents and catalysts were screened for the preparation of 4d, and the results are summarized in Table 1. It was found that reaction with [DMBSI]HSO4 as catalyst at solvent-free conditions is the most effective one with the hig-
-CHOC
Scheme 2. Synthesis of pyrido[2,3-d]pyrimidine derivatives 4a-h.
Table 1. Screening of various catalysts and solvents in the synthesis of 4d.
Entry	catalyst	solvent	Temperature (°C)	Time	Yield (%)
1	Fe+3@ Mont.	EtOH	80	5 h	30
2	KSF	EtOH	80	5 h	25
3	AcOH	d	100	6.5 h	65
4	ZnCl2	EtOH	80	24 h	10
5	P-TSA	EtOH	80	12 h	60
6		EtOH	80	24 h	trace
7	[TEBSA]HSO4b	EtOH	80	4 h	43
8	[MBSI]HSO44	EtOH	80	7.5 h	68
9	[DMBSI]HSO4	EtOH	80	4 min	82
10	[DMBSI]HSO4	H2O	80	6 min	40
11	[DMBSI]HSO4	CH2Cl2	25	30 min	25
12	[DMBSI]HSO4	d	25	30 min	30
13	[DMBSI]HSO4	d	80	< 1 min	87e
a Isolated yield. b AAA-triethyl-A-butanesulfonic acid ammonium hydrogen sulfate. c 1-methyl-A-butanesulfo-nic acid imidazolium hydrogen sulfate. d Solvent-free reaction. e Short reaction time (< 1 min) and almost the same yield (85%) also remains after three reaction cycles.
a
hest yield (87%) and the shortest reaction time (< 1 min) among selected solvents and catalysts (Table 1, entry 13).
The results of the reaction after 3 successive runs showed no significant loss of activity (Table 1, entry 13). After completion of the reaction, ionic liquid is easily separated from the reaction medium by washing with water (ionic liquid is soluble in water). The washed ionic liquid is distilled under vacuum to recover the ionic liquid for reuse in subsequent reactions.
We also verified the amount of catalyst needed for the preparation of 4d, and the best result was obtained by using 0.06 g [DMBSI]HSO4 per 1 mmol of substrate (Table 2).
Table 3: Synthesis of pyrido[2,3-rf]pyrimidine derivatives 4a-h.
Entry	Product	Ar	Time (min)	Yield (%)a
1	4a	C6H5	3	80
2	4b	4-MeC6H4	2	79
3	4c	4-FC6H4	< 1	95
4	4d	4-ClC6H4	< 1	90
5	4e	4-CNC6H,	< 1	93
6	4f	2,4-Cl2C6H3	< 1	95
7	4g	3-NO2C6H4	2	87
8	4h	4-CHOC6H4	3	84
a Isolated yield.
Table 2. Optimization of the amount of catalyst in the synthesis of 4d.
Catalyst (g)	Time (min)	Yield (%)a
0.01	30	trace
0.03	10	56
0.06	< 1	87
0.08	< 1	87
aIsolated yield.
Therfore, all reactions described in this report were performed under optimized conditions to afford pyri-do[2,3-d]pyrimidines 4a-h (Scheme 2) in high yields (79-95%) and short reaction times (< 1-3 min) (Table 3).
In order to extend the scope of this protocol for the synthesis of other derivatives of pyridopyrimidines, we investigated the reaction of 6-amino-2-(methylthio)pyrimi-din-4(3#)-one (1), heteroaromatic aldehydes (6) and Mel-drum's acid (5), in the presence of [DMBSI] HSO4 and obtained pyrido[2,3-d]pyrimidines 7a-e (Scheme 3) in high yields (80-90%) (Table 4).
Heteroaromatic aldehydes (6a-e) were prepared according to the known procedure.34 The mechanism of this
multi-component reaction (MCR) involves the reaction between Meldrum's acid (5) and heteroaromatic aldehydes (6a-e), resulting in arylidene intermediate, followed by Michael addition of enaminone 1, cyclization and removal of CO2 and acetone to form the reaction products (7a-e) (Scheme 4).
Electron-withdrawing substituents improved the efficiency of this cyclocondensation reaction (Table 3 and 4). The reaction is very clean and no side-products are formed. All of the synthesized pyrido[2,3-d]pyrimidines were characterized with elemental analyses, 1H and 13C NMR, and IR spectroscopy.
Table 4. Synthesis of pyrido[2,3-d]pyrimidine-4,7(3H,8H)-diones 7a-e.
Entry	Product	Ar	Time (min)	Yield (%)a
1	7a	C6H5	6	81
2	7b	4-OMeC6H4	6	80
3	7c	4-ClC6H46 4	5	84
4	7d	3-NOAH4	4	90
5	7e	4-NOAH4	4	86
a Isolated yield.
Ar = C6H5, p-ClC6H4, /?-OCH3C6H4, /7-N02C6H4, w-N02C6H4
Scheme 3. Synthesis of pyrido[2,3-d]pyrimidine-4,7(3H,8H)-diones 7a-e.
Scheme 4. Plausible mechanism for the synthesis of pyrido[2,3-d]pyrimidine-4,7(3H,8H)-diones 7a-e.
3. Experimental
Melting points were recorded on a Büchi B-545 apparatus in open capillary tubes. IR spectra were determined on a Shimadzo IR-470 spectrometer. and 13C NMR spectra were recorded on a 400 MHz Bruker DRX-400, using DMS0-d6 as solvent and TMS as an internal standard. Mass spectra were documented on an Agilent Technology (HP) mass spectrometer operating at an ionization potential of 70 eV. Elemental analyses were done on a Carlo-Erba EA1110CNN0-S analyzer and agreed with the calculated values. Chemicals were purchased from Merck and Fluka. All solvents used were dried and distilled according to standard procedures.
S03H-functionalized ionic liquid [DMBSI]HS04 was synthesized by adapting the reported procedure.35
3. 1. Synthesis 1,2-dimethyl-imidazoliumbuta-ne Sulfonate (DMIBS)
To a solution of 1,2-dimethyl-1H-imidazole (0.10 mol) in ethanol (25 mL) 0.1 mol 1,4-butanesultone was added in portions within 30 min, and the mixture was stirred for 48 h at room temperature (25 °C). The white precipitate thus formed was filtered and washed with petroleum ether. The product was recrystallized with EtOH, which gave DMIBS in 95 % yield as white solid with m.p. 268-270 °C.
3. 2. Synthesis of 1,2-dimethyl-N-butanesul-fonic Acid Imidazolium Hydrogen Sulfate [DMBSI]HSO4 Ionic Liquid
Equimolar amounts of 1,2-dimethylimidazoliumbu-tane sulfonate (DMIBS) and sulfuric acid solutions (96%)
were mixed and stirred for 6 h at 80 °C. The combined solution was then dried in a vacuum at 100 °C. The residue was washed repeatedly with diethyl ether to remove unreacted material and dried under vacuum again. The ionic liquid was obtained quantitatively in high purity as colorless viscose oil.
The spectral data for 1,2-dimethyl-N-butanesulfo-nic acid imidazolium hydrogen sulfate [DMBSI]HSO4: *H NMR (400 MHz, D2O): 51.45 (m, 2H, CH2), 1.68 (m, 2H, CH2), 2.32 (s, 3H, CH3), 2.66 (t, J = 7.6, CH2-S), 3.49 (s, 3H, CH3), 3.88 (t, J = 7.2, 2H, CH2-N), 7.05 (d, J = 2.0, 1H, CH=), 7.10 (d, J = 2.0, 1H, = CH); 13C NMR (100 MHz, D2O): 5 8.6, 20.9, 27.6, 34.4, 47.3, 50.0, 120.7, 122.0, 1424.1.
3. 3. General Procedure for Preparation of Compounds 4a-h and 7a-e
A mixture of equimolar amounts of 6-amino-2-(methylthio)pyrimidin-4(3H)-one (1) (1 mmol), ethylc-yanoacetate or meldrum's acid (2 or 5) (1 mmol) and aldehyde (3 or 6) (1 mmol) was added to a vial containing a magnetic stirring bar and [DMBSI]HSO4 (0.18 mmol, 0.06g) and heated at 80 °C in an oil bath. Stirring at 80 °C was continued until disappearance of the starting materials. At this stage, due to the poor solubility in the ionic liquid, the product appears as a precipitate. The reaction mixture was cooled and washed with water to extract the ionic liquid. The solid obtained was recry-stallized from ethanol to furnish the desired pure product.
The ionic liquid was recovered from the aqueous extracts by evaporation under reduced pressure, and reused in the next run.
Tetrahydro-2-(methylthio)-4,7-dioxo-5-phenylpyri-do[2,3-d]pyrimidine-6-carbomtrile (4a)
White solid, mp > 400 °C, IR (KBr): u 3150, 3050, 2960, 2880, 2220, 1630, 1530, 1500, 1490, 1340, 760, 700 cm-1; 1H NMR (400 MHz, DMSO-d6): 5 2.59 (s, 3H, CH3), 7.21-7.43 (m, 5H, Ar-H), 12.90 (bs. s, 1H, NH), 12.98 (br. s, 1H, NH) ppm; 13C NMR (100 MHz, DMSOd6): 513.4, 99.4, 102.7, 115.8, 127.7, 128.2, 129.0, 136.7, 155.9, 158.3, 160.5, 161.6, 167.3 ppm. Anal. Calcd. for C15H10N4O2S (310.33): C, 58.05; H, 3.25; N, 18.05; Found: C, 57.91; H, 3.11; N, 17.93.
3,4,7,8-Tetrahydro-2-(methylthio)-4,7-dioxo-5-p-tolyl pyrido[2,3-d]pyrimidine-6-carbomtrile (4b)
White solid, mp = 342-344 °C, IR (KBr): u 3030, 2900, 2750, 2220, 1630, 1540, 1460, 1350, 795 cm-1; 1H NMR (400 MHz, DMSO-d6): 5 2.41 (s, 3H, CH3), 2.59 (s, 3H, SCH3), 7.19 (d, J = 8.0 Hz, 2H, Ar-H), 7.24 (d, J = 8.0 Hz, 2H, Ar-H), 12.87 (bs. s, 1H, NH), 12.98 (br. s, 1H, NH) ppm; 13C NMR (100 MHz, DMSO-d6): 513.4, 21.5, 99.4, 102.8, 116.0, 127.7, 128.7, 133.7, 138.4, 155.9, 158.3, 160.5, 161.7, 167.2 ppm. Anal. Calcd. for C16H12N4O2S (324.36): C, 59.25; H, 3.73; N, 17.27; Found: C, 59.18; H, 3.75; N, 17.15.
5-(4-Fluorophenyl)-3,4,7,8-tetrahydro-2-(methylthio)-4,7-dioxopyrido[2,3-d]pyrimidine-6-carbomtrile (4c)
Yellow solid, mp = 389-392 °C, IR (KBr): u 3050, 2910, 2850, 2215, 1675, 1630, 1600, 1530, 1480, 1450, 1340, 1140, 825 cm-1; 1H NMR (400 MHz, DMSO-d6): 5 2.60 (s, 3H, CH3), 7.28 (t, J = 9.1 Hz, 2H, Ar6-H), 7.36-7.40 (m, 2H3, Ar-H), 12.99 (bs. s, 1H, NH), 13.02 (bs, 1H, NH) ppm; 13C NMR (100 MHz, DMSO-d6): 5 13.4, 99.5, 103.0, 115.1, 115.3, 115.8, 130.2 (d, 3JCF = 9 Hz), 132.9 (d, 4Jcf = 3.0 Hz), 157.1 (d, 1JCF = 242.0 Hz), 160.5 (d, 2Jcf = 15.0 Hz), 161.5, 164.0, 167.4 ppm. Anal. Calcd. for CC1F5H9FN4O2S (328.32): C, 54.87; H, 2.76; N, 17.06; Found: C, 54.64; H, 2.70; N, 16.88.
5-(4-Chlorophenyl)-3,4,7,8-tetrahydro-2-(methylthio)-4,7-dioxopyrido[2,3-d]pyrimidine-6-carbomtrile (4d)
White solid, mp = 324-326 °C, IR (KBr): u 3040, 2900, 2700, 2210, 1630, 1540, 1460, 1355, 800 cm-1; 1H NMR (400 MHz, DMSO-d6): 5 2.54 (s, 3H, CH3), 7.35 (br. s, 2H, Ar-H), 7.50 (bs, 2H, Ar-H), 13.0 (bs. s, 2H, NH) ppm; 13C NMR (100 MHz, DMSO-d6): 5 13.4, 99.4, 102.7, 115.8, 128.3, 129.7, 133.8, 135.6, 156.0, 158.5, 160.3, 160.4, 167.6 ppm. Anal. Calcd. for C15H9ClN4O2S (344.78): C, 52.25; H, 2.63; N, 16.25; Found1 C, 52.11; H, 2.48 N, 16.10.
5-(4-Cyanophenyl)-3,4,7,8-tetrahydro-2-(methylthio)-4,7-dioxopyrido[2,3-d]pyrimidine-6-carbomtrile (4e)
White solid, mp = 370-372 °C. IR (KBr): u 3100, 3000, 2800, 2200, 1650, 1570, 1535, 1440, 1400, 820 cm-1. 1H NMR (400 MHz, DMSO-d6): 5 2.40 (s, 3H,
CH3), 7.45 (d, J = 8.0 Hz, 2H, Ar-H), 7.87 (d, J = 8.0 Hz, 2H, Ar-H), 11.60 (bs. s, 2H, NH) ppm; 13C NMR (100 MHz, DMSO-d6): 5 13.6, 98.3, 99.6, 110.8, 116.6, 119.4,
128.7,	132.0, 143.8, 157.4, 160.4, 160.8, 164.0, 172.6 ppm. Anal. Calcd. for C16H9N5O2S (335.34); C, 57.31; H, 2.71; N, 20.88; Found: C, 57.38; H, 2.60; N, 20.89.
5-(2,4-Dichlorophenyl)-3,4,7,8-tetrahydro-2-(methylt-hio)-4,7-dioxopyrido[2,3-d]pyrimidme-6-carbomtrile
(4f)
Yellow solid, mp = 324-326, IR (KBr): u 3100, 2995, 2900, 2800, 2205, 1640, 1570, 1538, 1440, 1390, 818, 850 cm-1; 1H NMR (400 MHz, DMSO-d6): 5 2.61 (s, 3H, CH3), 7.40 (d, J = 8.4 Hz, 1H, Ar-H), 7.55 (m, 1H, Ar-H), 7.77 (d, J = 1.2 Hz, 1H, Ar-H), 13.15 (bs. s, 2H, NH) ppm; 13C NMR (100 MHz, DMSO-d6): 5 13.5, 99.5,
102.8,	115.1, 127.9, 129.0, 130.5, 132.0, 134.5, 135.0, 156.0, 157.3, 158.1, 160.3, 168.0 ppm. Anal. Calcd. for C15H8Cl2N4O2S (379.22): C, 47.51; H, 2.31; N, 14.77; Found: C, 447.35; H, 2.20; N, 14.72.
3,4,7,8-Tetrahydro-2-(methylthio)-5-(3-nitrophenyl)-4,7-dioxopyrido[2,3-d]pyrimidine-6-carbomtrile (4g)
Pale yellow solid, mp = 360-363 °C, IR (KBr): u 3030, 2920, 2700, 2205, 1640, 1530, 1460, 1345, 800, 720, 695 cm-1; 1H NMR (400 MHz, DMSO-d6): 5 2.61 (s, 3H, CH3), 7.67-7.84 (m, 2H, Ar-H), 8.26 (s, 1H, Ar-H), 8.33 (d, J = 7.2 Hz, 1H, Ar-H), 13.03 (bs. s, 2H, NH) ppm; 13C NMR (100 MHz, DMSO-d6): 5 13.5, 99.5, 102.8,
115.6,	123.1, 124.0, 130.1, 134.6, 138.3, 147.6, 156.0,
158.7,	158.8, 160.4, 167.8 ppm. Anal. Calcd. for C15H9N5O4S (355.33); C, 50.70; H, 2.55; N, 19.71; Found: C, 50.60; H, 2.43; N, 19.58.
5-(4-Formylphenyl)-3,4,7,8-tetrahydro-7-methylene-2-(methylthio)-4-oxopyrido [2,3-d]pyrimidine-6-carbo-nitrile (4h)
Pale yellow solid, mp = 347-349 °C, IR (KBr): u 3100, 3050, 2900, 2205, 2700, 2800, 1700, 1640, 1600, 1540, 1520, 1460, 1350, 818 cm-1; 1H NMR (400 MHz, DMSO-d6): 5 2.60 (s, 3H, CH3), 7.55 (d, J = 8.4 Hz, 2H, Ar-H), 8.14 (d, J = 8.4 Hz, 2H, Ar-H), 8.50 (s, 1H, CHO); 12.98 (br s, 1H, NH), 13.06 (bs. s, 1H, NH) ppm; 13C NMR (100 MHz, DMSO-d6): 5 13.5, 99.4, 103.3, 115.7, 116.2, 128.7, 130.8, 131.8, 141.8, 155.0, 156.0, 160.1, 160.4, 162.3 ppm. Anal. Calcd. for C16H10N4O3S (338.34): C, 56.80; H, 2.98; N, 16.56; Found: C, 5(5.68; H, 2.90; N, 16.44.
5,6-Dihydro-2-(methylthio)-5-(1,3-diphenyl-1ff-pyra-zol-5-yl)pyrido[2,3-d]pyrimidine-4,7(3#,8#)-dione (7a)
White solid, mp = 214-216 °C: IR (KBr): u 3490, 3380, 3050, 2960, 2700, 1705, 1640, 1575, 1540, 750, 695, 690 cm-1; 1H NMR (400 MHz, DMSO-d6): 5 2.40 (s, 3H, CH3), (dd, J = 15.2, 6.8 Hz, 1H, CH), 3.10 (dd, J = 15.2, 7.63 Hz, 1H, CH), 4.66 (t, J = 7.6 Hz, 1H, CH), 6.01
(s, 1H, =CH), 7.28-7.42 (m, 3H, Ar-H), 7.51 (t, J = 8.4 Hz, 2H, Ar-H), 7.73 (d, J = 7.2 Hz, 2H, Ar-H), 7.84 (d, J = 7.6 Hz, 2H, Ar-H), 8.38 (s, 1H, NH), 11.71 (bs. s, 1H, NH) ppm; 13C NMR (100 MHz, DMSO-d6): 512.8, 28.1, 37.0, 93.8, 118.4, 122.5, 126.4, 128.1, 128.2, 128.3, 128.6, 130.0, 134.0, 140.0, 150.8, 159.7, 162.6, 172.2 ppm. Anal. Calcd. for C23H19N5O2S (429.49): C, 64.32; H, 4.46; N, 16.31; Found: C, 64.20; H, 4.33; N, 16.43.
5,6-Dihydro-5-(3-(4-methoxyphenyl)-1-phenyl-1H-pyrazol-5-yl)-2-(methylthio)pyrido[2,3-d] pyrimidine-4,7(3H,8H)-dione (7b)
White solid, mp = 200-202 °C, IR (KBr): u 3490, 3390, 3050, 2920, 2700, 1718, 1620, 1610, 1570, 1540, 1500, 1240, 1020, 830, 770, 690 cm-1; 1H NMR (400 MHz, DMSO-d6): 5 2.40 (s, 3H, CH3), 3.03 (m, 2H, CH2), 3.98 (s, 3H, OMe), 4.63 (bs. s, 1H, CH), 6.02 (s, 1H, =CH), 6.95 (d, J = 7.6 Hz, 2H, Ar-H), 7.29 (m, 1H, Ar-H), 7.49 (m, 2H, Ar-H), 7.66 (d, J = 7.6 Hz, 2H, Ar-H), 7.83 (d, J = 7.6 Hz, 2H, Ar-H), 8.35 (s, 1H, NH), 11.74 (bs, 1H, NH) ppm; 13C NMR (100 MHz, DMSO-d6): 5 12.9, 28.2, 37.0, 55.6, 93.8, 114.0, 118.3, 122.1, 126.2, 126.4, 128.1, 129.6, 130.0, 140.1, 150.6, 159.3, 159.7, 162.6, 172.2 ppm. Anal. Calcd. for C24H21N5O3S (459.52): C, 62.73; H, 4.61; N, 15.24; Found: C, 62.82; H, 4.50; N, 15.31.
5-(3-(4-Chlorophenyl)-1-phenyl-1H-pyrazol-5-yl)-5,6-dihydro-2-(methylthio)pyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione (7c)
White solid, mp = 195-197 °C, IR (KBr): u 3480, 3390, 1720, 1610, 1520, 1500, 1025, 840, 755, 690 cm-1; 1H NMR (400 MHz, DMSO-d6): 5 2.39 (s, 3H, CH3S), 3.0 (dd, J = 14.8, 6.8 Hz, 1H, CH2, diastereotopic), 3.09 (dd, J = 14.8, 6.8 Hz, 1H, CH2, diastereotopic), 4.65 (t, J = 6.8 Hz, 1H, CH), 6.09 (s, 1H, = CH), 7.31 (t, J = 7.4 Hz, 1H, Ar-H), 7.43 (d, J = 8.0 Hz, 2H, Ar-H), 7.51 (t, J = 7.8 Hz, 2H, Ar-H), 7.73 (d, J = 8.4 Hz, 2H, Ar-H), 7.84 (d, J = 8.0 Hz, 2H, Ar-H), 8.40 (s, 1H, NH), 11.69 (bs. s, 1H, NH) ppm; 13C NMR (100 MHz, DMSO-d6): 512.8, 28.0, 37.0, 93.6, 118.4, 122.7, 126.5, 128.5, 128.6, 130.0, 132.7, 132.8, 139.4, 149.7, 159.7, 162.5, 172.1 ppm. Anal. Calcd. for C23H18ClN5O2S (463.94): C, 59.54; H, 3.91; N, 15.10; Found: C, 59.41; H, 3.85; N, 15.16.
5,6-Dihydro-2-(methylthio)-5-(3-(3-nitrophenyl)-1-phenyl-1H-pyrazol-5-yl)pyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione (7d)
Pale yellow solid, mp = 208-210 °C, IR (KBr): u 3490, 3390, 2920, 2800, 1700, 1620, 1565, 1525, 1340, 815, 760, 690 cm-1; 1H NMR (400 MHz, DMSO-d6): 5 2.37 (s, 3H, CH3S), 3.08 (m, 2H, CH2, diastereotop6ic), 4.69 (t, J = 7.2 Hz , 1H, CH), 6.10 (s, 1H, =CH), 7.34 (t, J = 7.4 Hz, 1H, Ar-H), 7.53 (t, J = 7.8 Hz, 2H, Ar-H), 7.66 (t, J = 8.0 Hz, 1H, Ar-H), 7.88 (d, J = 7.6 Hz, 2H, Ar-H), 8.08 (d, J = 7.6, Hz 1H, Ar-H), 8.21 (dd, J = 8.4, 1.2 Hz, 1H, Ar-H), 8.41 (s, 1H, Ar-H), 8.51 (s, 1H, NH), 11.66
(bs. s, 1H, NH) ppm; 13C NMR (100 MHz, DMSO-d6): 5 12.8, 27.8, 37.0, 93.6, 118.6, 122.8, 123.2, 126.7, 128.6, 130.0, 130.1, 134.9, 135.6, 139.8, 148.1, 149.0, 159.7, 162.5, 172.1 ppm. Anal. Calcd. for C23H18N6O4S (474.49): C, 58.22; H, 3.82; N, 17.71; Found: C, 58.30; H, 3.70; N, 17.55.
5,6-Dihydro-2-(methylthio)-5-(3-(4-nitrophenyl)-1-phenyl-1H-pyrazol-5-yl)pyrido[2,3-d]pyrimidine-4,7 (3H,8H)-dione (7e)
White solid, mp(dec.) = 360-362 °C, IR (KBr): u 3400, 3200, 1700, 1650 1520, 1350, 875, 790, 690 cm-1. Due to very low solubility the NMR data for this product cannot be reported. MS (m/z, %): 474 (M+, 0.9), 397 (2.8), 369 (24.5), 368 (52.6), 352 (1.8), 264 (23.5), 210 (2.3), 187 (6.5), 122 (4.9), 105 (15.5), 77 (37.4), 73 (16.5), 57 (100); Anal. Calcd. for C23H18N6O4S (474.49); C, 63.15; H, 5.30; N, 14.73; Found: C, 63.00; H, 5.22; N, 14.68.
4. Conclusion
In summary, we have developed a simple and efficient protocol for the synthesis of pyrido[2,3-d]pyrimi-dine derivatives in the presence of ionic liquid [DMBSI]HSO4 as a readily available catalyst. Mild reaction conditions, short reaction times, the easy work-up of the products, high yields, and reusability of the catalyst are the notable features of this protocol.
5. Acknowledgements
The authors are grateful to the Research Council of University of Guilan for the financial support of this research work.
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Povzetek
Avtorji v prispevku poročajo o regoselektivni pripravi pirido[2,3-d]pirimidinskih derivatov z dobrimi izkoristki s pomočjo uporabe enostopenjske trikomponentne kondenzacijske reakcije med 6-amino-2-(metiltio)pirimidin-4(3ff)-ono-nom, aromatskimi aldehidi in etilcianoacetatom oziroma meldrumovo kislino. Pri reakciji so kot katalizator uporabili ionsko tekočino (Br0nstedovo kislino); 1,2-dimetil-N-butansulfonsko kislino-imidazolijev hidrogensulfat ([DMBSI]HSO4. Reakcije potekajo hitro, pri milih pogojih, brez uporabe topila in z enostavno izolacijo produktov ter z enostavno reciklažo katalizatorja.