1368-1372An efficient, solvent-free and one-pot procedure for the synthesis of pyrido[2,3-d]pyrimidine derivatives by condensation
of aromatic aldehydes, malononitrile and 6-amino-1,3-dimethyl uracil at 90°C catalyzed by lactic acid as an inexpensive,
biological and eco-friendly compound is described. The remarkable benefits of this procedure are green and environmentally
friendly reaction conditions, high yields, short reaction time, simple methodology and easy workup

Hazeri, Nourallah

Lashkari, Mojtaba

Maghsoodlou, Malek Taher

Mollashahi, Ebrahim

Safarzaei, Mohyeddin

NOPR

Indian Journal of Chemistry Vol. 60B, October 2021, pp. 1368-1372 An efficient solvent-free synthesis of pyrido[2,3-d]pyrimidine derivatives utilizing lactic acid as green and eco-friendly catalyst Mohyeddin Safarzaeia, Ebrahim Mollashahi*a, Mojtaba Lashkarib, Malek Taher Maghsoodloua & Nourallah Hazeria a Department of Chemistry, Faculty of Sciences, University of Sistan and Baluchestan, P.O. Box 98135-674, Zahedan, Iran b Faculty of Sciences, Velayat University, Iranshahr, Iran E-mail: mollashahi39@chem.usb.ac.irReceived 28 February 2020; accepted (revised) 26 August 2021 An efficient, solvent-free and one-pot procedure for the synthesis of pyrido[2,3-d]pyrimidine derivatives by condensation of aromatic aldehydes, malononitrile and 6-amino-1,3-dimethyl uracil at 90°C catalyzed by lactic acid as an inexpensive, biological and eco-friendly compound is described. The remarkable benefits of this procedure are green and environmentally friendly reaction conditions, high yields, short reaction time, simple methodology and easy workup. Keywords: Lactic acid, 6-amino-1,3-dimethyluracil, aryl aldehyde, malononitrile, solvent-free conditions Multicomponent reactions (MCRs) have growing importance for several reasons including atom economy, reduced steps of work up, time saving, simple reaction design and minimized waste generation1. The first MCR was reported by Strecker for the synthesis of amino acids2. Pyrido[2,3-d]pyrimidines with uracil core have receivedconsiderable attention because of their biological andpharmacological activities for example, antitumor3,antihypertension4, antibacterial5, antifungal6 andantimicrobial properties7. Uracil derivatives are thebuilding blocks for the synthesis of N-containing speciesof biological and pharmacological significance8.All compounds of pyrazolopyrimidines9, xanthinederivatives10. Pyrazolopyridines11 and pyramid-dopyrimidines12 have been synthesized by thefunctionalization of uracil derivatives (Figure 1).Several synthetic methodologies have been reportedfor the preparation of them such as TEBAC13, nano-MgO14, microwave irradiation15, electrolysis16,L-proline17 and ionic liquid18. However, many of thesemethods have limitations such as low yields, longtime and specific conditions.In continuation of our researches on MCRs19-26, herein, we describe the efficient and simple synthesis of highly functionalized pyrido[2,3 d]pyrimidines by three component reactions of 6-aminouracil with malononitrile and aldehydes at 90°C to synthesize pyrido[2,3 d]pyrimidines in good yields (Scheme I). Results and Discussion At first, we optimized the reaction conditions in the preparation of pyrido[2,3-d]pyrimidines by performing the condensation of malononitrile, 4-chlorobenzaldehyde and 6-amino-1,3-dimethyluracil utilizing the lactic acid under various conditions (Table I). The best results were obtained at 90°C under solvent-free conditions (Table I, entries 12). After optimization of the reaction conditions, we employed several aromatic aldehydes containing electron-withdrawing or electron-releasing groups for the synthesis of the other derivatives under optimized condition. Table II show that all products were obtained successfully in short reaction time and good  Figure 1 — Some examples of biologically relevant compoundshaving pyrido[2,3-d]pyrimidine skeleton SAFARZAEI et al.: LACTIC ACID AS ECO-FRIENDLY CATALYST   1369 yields. It was shown that the aldehydes with electron-withdrawing groups gave shorter times and  good yields than aldehydes with electron-releasing groups.  To demonstrate the merit of our work, we compared the results of this work with the literature as shown in Table III. The data in Table III show that lactic acid can act as an efficient catalyst with respect   Scheme I — Synthesis of pyrido[2,3-d]pyrimidine derivatives  Table I — Effect of the solvent, temperature and amount of the catalyst in the synthesis of compound 4f Entry Solvent Temperature (°C) Catalyst (mol %) Time (min) Isolated Yield (%)a 1 H2O 70 10 60 58 2 EtOH 70 10 60 63 3 CHCl3 70 10 70 54 4 THF 70 10 70 48 5 − 70 10 45 68 6 − RT 10 120 Trace 7 − 50 10 65 60 8 − 80 10 35 88 9 − 90 10 25 91 10 − 100 10 20 89 11 − 90 5 30 90 12 − 90 15 20 94 13 − 90 20 20 92  Table II — Synthesis of pyrido[2,3-d]pyrimidines utilizing the lactic acid in solvent-free conditions Entry Product Time (min) Isolated Yield (%)a m.p. (°C) Found m.p. (°C) Reported [Ref] 1 4a, Ar = Ph 30 90 >300 >30018 2 4b, Ar = 4-MeC6H4 40 88 >300 >30013 3 4c, Ar = 4-MeOC6H4 35 89 >300 >30013 4 4d, Ar = 2-ClC6H4 25 93 >300 >30014 5 4e, Ar = 3-ClC6H4 30 91 >300 >30014 6 4f, Ar = 4-ClC6H4 20 94 >300 >30014 7 4g, Ar = 3-BrC6H4 30 92 >300 >30018 8 4h, Ar = 4-BrC6H4 20 93 >300 >30013 9 4i, Ar = 4-FC6H4 20 94 >300 >30018 12 4j, Ar = 3-FC6H4 30 92 >300 This work 13 4k, Ar = 2-MeC6H4 30 91 >300 This work 14 4l, Ar = 3-Pyridyl 25 92 290-292 This work 15 4m, Ar = 4-Pyridyl 25 93 >300 This work 16 4n, Ar = 2-Thienyl 30 91 >300 This work  Table III — Comparison of lactic acid with previously reported catalysts for the synthesis of compound 4f Entry Catalyst Time (min) Conditions Yield (%) Ref. 1 TEBAC 720 H2O, 90°C 96 13 2 Electrolysis 20 EtOH, KBr 71 16 3 Nano-MgO 15 H2O, 80°C 90 14 5 Lactic acid 20 Solvent free, 90°C 94 Present work  INDIAN J. CHEM., SEC B, OCTOBER 2021   1370to reaction yields and the obtained products. The products 4l-p are new compounds which were characterized by IR, 1H and 13C NMR and MS.  Experimental Section All the chemicals were purchased from chemical producers Merck or Fluka and used without further purification. Melting points and IR spectra of all compounds were determined using an FT-IR-JASCO-460 plus spectrometer and Electrothermal 9100 apparatus and are uncorrected. The 1H and 13C NMR spectra of compounds were recorded on a Bruker DRX-300 Avance instrument in DMSO-d6 at 300 MHz. Vincinal aromatic hydrogen coupling constants were in the range of 6-8 Hz. Mass spectra were obtained on the Sciex-3200 Technology spectrometer operating at an ionization potential of 70 eV.  General procedure for the synthesis of 2-aminopyrimidinomethylnaphthols To a mixture of aromatic aldehyde (1.0 mmol), malononitrile (1.0 mmol) and 6-amino-1,3-dimethyluracil (1.0 mmol), lactic acid (15 mol %) were added. The mixture was stirred at 90°C and reaction progress was monitored through TLC. After completion of the reaction, the mixture was cooled and washed with water. Lactic acid was removed from the mixture. The filter cake obtained was recrystallized from ethanol to obtain the pure product.  7-Amino-1,2,3,4-tetrahydro-1,3-dimethyl-2,4-dioxo- 5-phenylpyrido[2,3-d]pyrimidine-6-carbonitrile, 4a IR (KBr): 3452, 3317, 3223, 2212, 1716, 1667, 1624, 1557, 1508, 1439, 1369, 1309 cm−1; 1H NMR (300 MHz, DMSO-d6): δ 3.09 (s, CH3, 3H), 3.52 (s, CH3, 3H), 7.10-7.46 (5H, Haromatic), 7.95 (s, NH2, 2H,).  7-Amino-1,2,3,4-tetrahydro-1,3-dimethyl-2,4-dioxo-5-p-tolylpyrido[2,3-d]pyrimidine-6-carbonitrile, 4b IR (KBr): 3457, 3310, 3219, 2212, 1716, 1667, 1624, 1563, 1509, 1440, 1367 cm−1; 1H NMR (300 MHz, DMSO-d6): δ 2.39 (s, CH3, 3H), 3.09 (s, CH3, 3H), 3.51 (s, CH3, 3H), 7.11 (d, Haromatic, 2H,), 7.23 (d, Haromatic, 2H), 7.85 (s, NH2, 2H).  7-Amino-1,2,3,4-tetrahydro-5-(4-methoxyphenyl)-1,3-dimethyl-2,4-dioxopyrido[2,3-d]pyrimidine-6-carbonitrile, 4c IR (KBr): 3458, 3316, 3218, 2213, 1714, 1664, 1622, 1550, 1506, 1435, 1367, 1291 cm−1; 1H NMR (300 MHz, DMSO-d6): δ 3.09 (s, CH3, 3H), 3.51  (s, CH3, 3H), 3.83 (s, CH3, 3H), 6.97 (d, Haromatic, 2H), 7.16 (d, Haromatic, 2H), 7.82 (s, NH2, 2H).  7-Amino-5-(2-chlorophenyl)-1,2,3,4-tetrahydro-1,3-dimethyl-2,4-dioxopyrido[2,3-d]pyrimidine-6-carbonitrile, 4d IR (KBr): 3455, 3367, 3273, 2254, 1689, 1667, 1645, 1583, 1496, 1445, 1380, 1352, 1298, 1271 cm−1.  7-Amino-5-(3-chlorophenyl)-1,2,3,4-tetrahydro-1,3-dimethyl-2,4-dioxopyrido[2,3-d]pyrimidine-6-carbonitrile, 4e IR (KBr): 3397, 3328, 3224, 2224, 1712, 1662, 1630, 1557, 1507, 1435, 1366, 1308, 1288 cm−1.  7-Amino-5-(4-chlorophenyl)-1,2,3,4-tetrahydro-1,3-dimethyl-2,4-dioxopyrido[2,3-d]pyrimidine-6-carbonitrile, 4f IR (KBr): 3461, 3320, 3220, 2214, 1715, 1662, 1622, 1568, 1548, 1509, 1494, 1369, 1301 cm−1; 1H NMR (300 MHz, DMSO-d6): δ 3.09 (s, CH3, 3H), 3.51 (s, CH3, 3H), 7.26 (d, Haromatic, 2H), 7.49 (d, Haromatic, 2H), 7.95 (s, NH2, 2H).  7-Amino-5-(3-bromophenyl)-1,2,3,4-tetrahydro-1,3-dimethyl-2,4-dioxopyrido[2,3-d]pyrimidine-6-carbonitrile, 4g IR (KBr): 3460, 3317, 3222, 2215, 1717, 1660, 1623, 1565, 1515, 1479, 1443, 1371, 1279 cm−1. 7-Amino-5-(4-bromophenyl)-1,2,3,4-tetrahydro-1,3-dimethyl-2,4-dioxopyrido[2,3-d]pyrimidine-6-carbonitrile, 4h IR (KBr): 3460, 3313, 3220, 2960, 2214, 1715, 1663, 1623, 1569, 1546, 1509, 1493, 1438, 1369, 1277 cm−1; 1H NMR (300 MHz, DMSO-d6): δ 3.09  (s, CH3, 3H), 3.51 (s, CH3, 3H), 7.21 (d, Haromatic, 2H), 7.63 (d, Haromatic, 2H), 7.93 (s, NH2, 2H).  7-Amino-5-(4-fluorophenyl)-1,2,3,4-tetrahydro-1,3-dimethyl-2,4-dioxopyrido[2,3-d]pyrimidine-6-carbonitrile, 4i IR (KBr): 3401, 3329, 3224, 2228, 1715, 1671, 1634, 1598, 1557, 1510, 1440, 1368, 1311 cm−1; 1H NMR (300 MHz, DMSO-d6): δ 3.10 (s, CH3, 3H), 3.52 (s, CH3, 3H), 7.27-7.32 (m, Haromatic, 4H), 7.90 (s, NH2, 2H).  7-Amino-5-(3-fluorophenyl)-1,2,3,4-tetrahydro-1,3-dimethyl-2,4-dioxopyrido[2,3-d]pyrimidine-6-carbonitrile, 4j IR (KBr): 3487, 3400, 3324, 3222, 3075, 2219, 1715, 1670, 1631, 1563, 1492, 1430, 1391,  1367 cm−1; 1H NMR (300 MHz, DMSO-d6): δ 3.10 (s, SAFARZAEI et al.: LACTIC ACID AS ECO-FRIENDLY CATALYST   1371CH3, 3H), 3.52 (s, CH3, 3H), 7.08-7.31 (m, Haromatic, 3H), 7.46-7.53 (m, Haromatic, 1H), 7.95 (s, NH2, 2H); 13C NMR (75 MHz, DMSO-d6): δ 28.1, 30.0, 88.8, 99.1, 114.8, 115.1, 115.3, 115.5, 123.9, 130.3, 130.5, 139.8, 140.0, 151.3, 154.0, 158.1, 158.8, 160.4, 160.6, 163.7; MS: m/z (%) 185.1 (4), 256.2 (6), 274.2 (15), 282.2 (20), 290.2 (12), 302.2 (25), 304.2 (100), 326.1 (25), 327.1 (M+, 3).  7-Amino-1,2,3,4-tetrahydro-1,3-dimethyl-2,4-dioxo- 5-o-tolylpyrido[2,3-d]pyrimidine-6-carbonitrile, 4k IR (KBr): 3455, 3311, 3217, 2953, 2213, 1715, 1655, 1622, 1564, 1546, 1494, 1435, 1370, 1278 cm−1; 1H NMR (300 MHz, DMSO-d6): δ 2.02 (s, CH3, 3H), 3.09 (s, CH3, 3H), 3.53 (s, CH3, 3H), 7.01 (d, Haromatic, 1H), 7.21-7.34 (m, Haromatic, 3H), 7.90 (s, NH2, 2H); 13C NMR (75 MHz, DMSO-d6): δ 19.5, 28.1, 30.0, 88.6, 99.3, 115.4, 125.9, 127.0, 128.4, 129.8, 134.3, 137.7, 151.3, 154.1, 158.8, 159.6, 160.9; MS: m/z (%) 59.0 (4), 62.0 (100), 88.9 (3), 97.0 (7), 255.2 (2), 320.4 ([M-H]+, 20).  7-Amino-1,2,3,4-tetrahydro-1,3-dimethyl-2,4-dioxo- 5-(pyridin-3-yl)pyrido[2,3-d]pyrimidine-6-carbonitrile, 4l IR (KBr): 3350, 3198, 2214, 1709, 1642, 1575, 1480, 1444, 1418, 1370 cm−1; 1H NMR (300 MHz, DMSO-d6): δ 3.10 (s, CH3, 3H), 3.52 (s, CH3, 3H), 7.47 (t, Haromatic, 1H), 7.72-7.76 (m, Haromatic, 1H), 7.99 (s, NH2, 2H), 8.46 (d, Haromatic, 1H), 8.63 (dd, Haromatic, 1H); 13C NMR (75 MHz, DMSO-d6): δ 28.2, 30.1, 89.0, 99.2, 115.6, 123.2, 133.7, 135.6, 147.9, 149.6, 151.2, 154.0.  7-Amino-1,2,3,4-tetrahydro-1,3-dimethyl-2,4-dioxo- 5-(pyridin-4-yl)pyrido[2,3-d]pyrimidine-6-carbonitrile, 4m IR (KBr): 3382, 3040, 2220, 1708, 1666, 1602, 1571, 1539, 1519, 1440, 1367 cm−1; 1H NMR (300 MHz, DMSO-d6): δ 3.10 (s, 3H, CH3), 3.52 (s, 3H, CH3), 7.29 7.31 (dd, Haromatic, 2H), 8.03 (s, NH2, 2H), 8.66-8.68 (dd, Haromatic, 2H); 13C NMR (75 MHz, DMSO-d6): δ 28.1, 30.0, 88.0, 98.7, 115.3, 122.6, 145.9, 149.6, 151.3, 154.0, 156.8, 158.9, 160.7; MS: m/z (%) 59.0 (5), 62.0 (100), 89.0 (3), 255.2 (5), 307.2 ([M-H]+, 12).  7-Amino-1,2,3,4-tetrahydro-1,3-dimethyl-2,4-dioxo- 5-(thiophen-2-yl)pyrido[2,3-d]pyrimidine-6-carbonitrile, 4n IR (KBr): 3446, 3315, 3222, 2957, 2212, 1715, 1667, 1623, 1557, 1510, 1450, 1427, 1367, 1277 cm−1; 1H NMR (300 MHz, DMSO-d6): δ 3.12 (s, CH3, 3H), 3.50 (s, CH3, 3H), 7.07-7.15 (m, Haromatic, 2H), 7.72-7.74 (dd, Haromatic, 1H), 7.91 (s, NH2, 2H); 13C NMR (75 MHz, DMSO-d6): δ 28.2, 30.1, 90.1, 100.0, 115.5, 127.1, 127.9, 128.1, 136.7, 151.2, 152.6, 154.1, 158.5, 160.5; MS: m/z (%) 102.2 (12), 230.3 (15), 274.2 (100), 282.3 (35), 304.3 (90), 314.1 ([M+H]+, 15).  Conclusion In summary, we have demonstrated a highly efficient one-pot procedure for the three-component synthesis of pyrido[2,3-d]pyrimidines via condensation of an aldehyde, malononitrile and 6-amino-1,3-dimethyluracil in the presence of the lactic acid as an environmentally benign catalyst in solvent-free conditions. Lactic acid is green, inexpensive and readily commercially available catalyst. Easy and clean preparation, operationally simple, good yields, reasonable time, product purity, non-toxic and mild conditions are advantages of this method.  Acknowledgment The authors gratefully acknowledge financial support from the Research Council of the University of Sistan and Baluchestan.  References 1 Domling A & Ugi I, Angew Chem Int Ed, 39 (2000) 3168. 2 Strecker A, Liebigs Ann Chem, 74 (1850) 27. 3 Grivaky E M, Lee S, Siyal C W, Duch D S & Nichol C A, J Med Chem, 23 (1980) 327. 4 Bennett L R, Blankley C J, Fleming R W, Smith R D & Tessman D K, J Med Chem, 24 (1981) 382. 5 Ravi Kanth S, Venkat Reddy G, Hara Kishore K, Shanthan Rao P, Narsaiah B & Surya Narayana Murthy U, Eur J Med Chem, 41 (2006) 1011. 6 Quiroga J, Cisneros C, Insuasty B, Abonia R, Cruz S, Nogueras M, dela Torre J M, Sortino M & Zacchino S,  J Heterocycl Chem, 43 (2006) 299. 7 Donkor I O, Klein C L, Liang L, Zhu N, Bradley E & Clark A M, J Pharm Sci, 84 (1995) 661. 8 Bradshaw T K & Hutchinson D W, Chem Soc Rev, 6 (1977) 43. 9 Bhuyan P, Boruah R C & Sandhu J S, J Org Chem, 55 (1990) 568. 10 Muller C E, Geis U, Hipp J, Schobert U, Frobenius W, Pawlowski M, Suzuki F & Sandoval Ramirez J, J Med Chem, 40 (1997) 4396. 11 Quiroga J, Cruz S, Insuasty B & Abonia R, J Heterocycl Chem, 38 (2001) 53. 12 Thakur A J, Saikia P, Prajapati D & Sandhu J S, Synlett, 2001 (2001) 1299. 13 Shi D, Ji S, Niu L, Shi J & Wang X, J Heterocycl Chem, 44 (2007) 1083. 14 Mossafaii-Rad A & Mokhtary M, Int Nano Lett, 5 (2015) 109. INDIAN J. CHEM., SEC B, OCTOBER 2021   137215 Agarwal A & Chauhan P, Tetrahedron Lett, 46 (2005)  1345. 16 Kazemi-Rad R, Azizian J & Kefayati H, J Serb Chem Soc, 81 (2016) 29. 17 Samai S, Chandra-Nandi G, Chowdhury S & Shankar-Singh M, Tetrahedron, 67 (2011) 5935. 18 Goli-Jolodar O, Shirini F & Seddighi M, Chin J Catal, 38 (2017) 1245. 19 Safarzaei M, Maghsoodlou M T, Mollashahi E, Hazeri N & Lashkari M, J Chin Chem Soc, 66 (2019) 543. 20 Fatahpour M, Hazeri N, Maghsoodlou M T & Lashkari M,  J Chin Chem Soc, 64 (2017) 1071. 21 Milani J, Maghsoodlou M T, Hazeri N & Nasiri M, J Iran Chem Soc, 16 (2019) 1651. 22 Shirzaei M, Mollashahi E, Maghsoodlou M T & Lashkari M, J Saudi Chem Soc, 24 (2020) 216. 23 Noori-Sadeh F, Lashkari M, Hazeri N, Fatahpour M & Maghsoodlou M T, Org Chem Res, 5 (2019) 233. 24 Fatahpour M, Hazeri N, Maghsoodlou M T & Lashkari M,  J Iran Chem Soc, 16 (2019) 111. 25 Safarzaei M, Maghsoodlou M T, Mollashahi E, Hazeri N & Lashkari M, Res Chem Intermed, 44 (2018) 7449. 26 Mohamadpour F, Maghsoodlou M T, Lashkari M, Heydari R & Hazeri N, Org Prep Proced Int, 51 (2019) 456.   

An efficient solvent-free synthesis of pyrido[2,3-d]pyrimidine derivatives utilizing lactic acid as green and eco-friendly catalyst

http://nopr.niscair.res.in/bitstream/123456789/58322/1/IJC%20%28Section%20B%29%2c%2060B%2c%201368-1372%20%28Oct%2c2021%29.pdf

An efficient solvent-free synthesis of pyrido[2,3-d]pyrimidine derivatives utilizing lactic acid as green and eco-friendly catalyst

Abstract

Similar works

Full text

Available Versions

NOPR