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BY-NC-ND 3.0 license Open Access Published by De Gruyter August 12, 2014

Solvent-free multicomponent assembling of aldehydes, N,N′-dialkyl barbiturates and malononitrile: fast and efficient approach to pyrano[2,3-d]pyrimidines

Michail N. Elinson, Fedor V. Ryzhkov, Valentina M. Merkulova, Alexey I. Ilovaisky and Gennady I. Nikishin

Abstract

Potassium fluoride-catalyzed solvent-free multicomponent reaction of aldehydes, N,N′-dialkyl barbiturates and malononitrile results in the fast (15 min) and efficient (yields 89–95%) formation of substituted pyrano[2,3-d]pyrimidines. The improved synthetic methodology for this class of bioactive compounds is important from the viewpoint of diversity-oriented large-scale processes and represents an environmentally benign solvent-free synthetic concept for multicomponent reactions strategy.

Introduction

Pyrano[2,3-d]pyrimidines have received considerable attention owing to their wide range of diverse pharmacological activity. They are nicotinic acid receptor (NAR) agonists [1] and show antitumor [2], hepatoprotective [3], antibronchitic [4], and anti-AIDS activity [5], among others.

The procedures for the preparation of pyrano[2,3-d]pyrimidines usually include the reaction of benzylidenemalononitriles with barbiturates in the presence of base catalysts [6, 7]. Multicomponent procedures have also been suggested for synthesis of pyrano[2,3-d]pyrimidines from aldehydes, malononitrile and N,N′-dialkyl barbiturates, using polyethylene glycol-stabilized Ni(0) nanoparticles in ethylene glycol [8], with triethylamine under sonication [9], in ethanol under electrolysis conditions [10] and under microwave radiation [11]. All these procedures for the synthesis of pyrano[2,3-d]pyrimidines have merits, but the fast, facile, and environmentally benign multicomponent solvent-free methodology is yet not known and should be developed.

Considering our preliminary results on the solvent-free transformation of C–H acids and salicylaldehydes [12–14] as well as the certain biomedical application of pyrano[2,3-d]pyrimidines mentioned above, it was of interest to design a convenient solvent-free methodology for the efficient synthesis of substituted pyrano[2,3-d]pyrimidines based on multicomponent reaction of aldehydes, N,N′-dialkyl barbiturates and malononitrile.

Results and discussion

We report the results on a fast multicomponent transformation of aldehydes 1a–h, N,N′-dialkyl barbiturates 2a,b and malononitrile into substituted pyrano[2,3-d]pyrimidines 3a–k under solvent-free conditions (Scheme 1).

Scheme 1

Scheme 1

Solvent-free reaction of aldehyde 1a, N,N′-dimethylbarbituric acid 2a and malononitrile without catalyst at 60°C after 15 min resulted in the formation of pyrano[2,3-d]pyrimidine 3a in the low yield of 15%. In the presence of 5 mol% of NaOAc as catalyst, under otherwise identical conditions, pyrano[2,3-d]pyrimidine 3a was obtained in 39% yield. Using 10 mol% and 30 mol% of NaOAc led to 3a in 51% and 65% yields, respectively. In the presence of 5% of KF (potassium fluoride) as catalyst the yield of 3a was 71%. Finally, at 60°C after 15 min the excellent yield of 95% of 3a was obtained with 10 mol% of KF.

By using the optimized conditions of 10 mol% of KF as catalyst at 60°C with 15 min reaction time, other substituted pyrano[2,3-d]pyrimidines 3a–k were obtained in yields of 89–95%. These high yields ensured analytical purity of the products after a simple workup without crystallization. Thus, this solvent-free procedure for synthesis of substituted pyrano[2,3-d]pyrimidines 3a–k developed by us is one step closer to the ‘ideal synthesis’ [15].

With the above results taken into consideration, the following mechanism for the potassium fluoride catalyzed multicomponent transformation of aldehydes 1, N,N′-dialkyl barbituric acids 2 and malononitrile into substituted pyrano[2,3-d]pyrimidines 3 can be suggested (Scheme 2). The initiation step of the catalytic cycle begins with the deprotonation of a molecule of N,N′-dialkyl barbituric acid 2 by the action of potassium fluoride, which generates the anion A of N,N′-dialkyl barbituric acid. Then Knoevenagel condensation of aldehyde 1 with barbituric acid anion A takes place with the elimination of hydroxide anion and formation of corresponding 5-benzylidenepyrimidine-2,4,6(1H,3H,5H)-trione 4. The subsequent hydroxide-promoted Michael addition of malononitrile to electron deficient Knoevenagel adduct 4 followed by intramolecular cyclization leads to corresponding pyrano[2,3-d]pyrimidine 3 with regeneration of barbituric acid anion A at the last step. Generation of the intermediate products B and C in this cascade of reactions can be noted.

Scheme 2

Scheme 2

Conclusion

Potassium fluoride (KF) is an efficient catalyst for selective solvent-free multicomponent transformation of aldehydes, N,N′-dialkyl barbituric acids and malononitrile into substituted pyrano[2,3-d]pyrimidine-6-carbonitriles in excellent (89–95%) yields. This new process opens an efficient and convenient solvent-free multicomponent way to synthesize substituted pyrano[2,3-d]pyrimidines – the promising compounds for a variety of biomedical applications.

Experimental

All melting points were measured with a Gallenkamp melting point apparatus and are uncorrected. 1H NMR (300 MHz) spectra were recorded with a Bruker Avance II-300 at ambient temperature in DMSO-d6 solutions.

General procedure for 3a–k

A mixture of benzaldehyde 1a–h (5 mmol), N,N′-dialkyl barbituric acid 2a,b (5 mmol), malononitrile (5 mmol) and potassium fluoride (KF; 0.029 g, 0.5 mmol) was stirred at 60°C for 15 min, and then cooled to 20°C. Water (10 mL) was added, the mixture was stirred for 15 min and filtered to isolate the solid product, which was washed with water (2 × 5 mL), ice-cold ethanol (5 mL), and dried under reduced pressure.

7-Amino-1,3-dimethyl-2,4-dioxo-5-phenyl-1,3,4,5-tetrahydro-2H-pyrano[2,3-d]pyrimi-dine-6-carbonitrile (3a)

This compound was obtained from 1a and 2a; yield 1.47 g (95%); mp 219–222°C (lit [11] mp 210°C); 1H NMR: δ 3.08 (s, 3H, CH3), 3.36 (s, 3H, CH3), 4.32 (s, 1H, CH), 7.15–7.39 (m, 7H, Ar, NH2).

7-Amino-1,3-dimethyl-5-(4-methylphenyl)-2,4-dioxo-1,3,4,5-tetrahydro-2H-pyrano[2,3-d]pyrimidine-6-carbonitrile (3b)

This compound was obtained from 1b and 2a; yield 1.48 g (91%); mp 202–203°C (lit [10] mp 203°C); 1H NMR: δ 2.25 (s, 3H, CH3), 3.08 (s, 3H, CH3), 3.35 (s, 3H, CH3), 4.28 (s, 1H, CH), 7.05–7.15 (m, 4H, Ar), 7.28 (s, 2H, NH2).

7-Amino-5-(4-methoxyphenyl)-1,3-dimethyl-2,4-dioxo-1,3,4,5-tetrahydro-2H-pyrano-[2,3-d]pyrimidine-6-carbonitrile (3c)

This compound was obtained from 1c and 2a; yield 1.53 g (90%); mp 225–226°C (lit [10] mp 225–227°C); 1H NMR: δ 3.15 (s, 3H, CH3), 3.39 (s, 3H, CH3), 3.68 (s, 3H, OCH3), 4.36 (s, 1H, CH), 6.32 (s, 2H, NH2), 6.74 (d, J = 8.4 Hz, 2H, Ar), 7.12 (d, J = 8.4 Hz, 2H, Ar).

7-Amino-5-(4-fluorophenyl)-1,3-dimethyl-2,4-dioxo-1,3,4,5-tetrahydro-2H-pyrano[2,3-d]pyrimidine-6-carbonitrile (3d)

This compound was obtained from 1d and 2a; yield 1.51 g (92%); mp 229–232°C (lit [10] mp 230–232°C); 1H NMR: δ 3.13 (s, 3H, CH3), 3.39 (s, 3H, CH3), 4.38 (s, 1H, CH), 6.69 (s, 2H, NH2), 6.90 (t, J = 8.7 Hz, 2H, Ar), 7.19 (dd, J = 8.1 Hz and 5.1 Hz, 2H, Ar).

7-Amino-5-(2-chlorophenyl)-1,3-dimethyl-2,4-dioxo-1,3,4,5-tetrahydro-2H-pyrano[2,3-d]pyrimidine-6-carbonitrile (3e)

This compound was obtained from 1e and 2a; yield 1.57 g (91%); mp 236–238°C (lit [10] mp 237–238°C); 1H NMR: δ 3.07 (s, 3H, CH3), 3.37 (s, 3H, CH3), 4.87 (s, 1H, CH), 7.16–7.42 (m, 6H, Ar, NH2).

7-Amino-5-(4-chlorophenyl)-1,3-dimethyl-2,4-dioxo-1,3,4,5-tetrahydro-2H-pyrano[2,3-d]pyrimidine-6-carbonitrile (3f)

This compound was obtained from 1f and 2a; yield 1.60 g (93%); mp 239–241°C (lit [16] mp 241–242°C); 1H NMR: δ 3.08 (s, 3H, CH3), 3.35 (s, 3H, CH3), 4.35 (s, 1H, CH), 7.18–7.47 (m, 6H, Ar, NH2).

7-Amino-5-(3-bromophenyl)-1,3-dimethyl-2,4-dioxo-1,3,4,5-tetrahydro-2H-pyrano[2,3-d]pyrimidine-6-carbonitrile (3g)

This compound was obtained from 1g and 2a; yield 1.79 g (92%); mp 215–217°C (lit [10] mp 217°C); 1H NMR: δ 3.16 (s, 3H, CH3), 3.40 (s, 3H, CH3), 4.38 (s, 1H, CH), 6.47 (s, 2H, NH2), 7.11 (t, J = 7.3 Hz, 1H, Ar), 7.19 (d, J = 7.3 Hz, 1H, Ar), 7.27 (d, J = 8.0 Hz, 1H, Ar), 7.44 (s, 1H, Ar).

7-Amino-1,3-dimethyl-5-(4-nitrophenyl)-2,4-dioxo-1,3,4,5-tetrahydro-2H-pyrano[2,3-d]pyrimidine-6-carbonitrile (3h)

This compound was obtained from 1h an 2a; yield 1.69 g (95%); mp 211–214°C (lit [10] mp 212–214°C); 1H NMR: δ 3.06 (s, 3H, CH3), 3.35 (s, 3H, CH3), 4.51 (s, 1H, CH), 7.49 (s, 2H, NH2), 7.55 (d, J = 8.1 Hz, 2H, Ar), 8.15 (d, J = 8.1 Hz, 2H, Ar).

7-Amino-1,3-diethyl-2,4-dioxo-5-phenyl-1,3,4,5-tetrahydro-2H-pyrano[2,3-d]pyrimidine-6-carbonitrile (3i)

This compound was obtained from 1a and 2b; yield 1.51 g (89%); mp 147–150°C; 1H NMR: δ 1.01 (t, J = 7.3 Hz, 3H, CH3), 1.22 (t, J = 7.3 Hz, 3H, CH3), 3.67–3.82 (m, 2H, CH2), 3.90–4.05 (m, 2H, CH2), 4.33 (s, 1H, CH), 7.15–7.40 (m, 7H, Ar, NH2); 13C NMR (75 MHz, DMSO-d6): δ 12.6, 13.8, 35.8, 36.4, 37.8, 58.6, 89.2, 119.0, 126.7, 127.2 (2C), 128.3 (2C), 144.0, 149.1, 150.9, 157.7, 160.0 ppm; IR (KBr): ν 3382, 3187, 2208, 1687, 1632, 1486, 1382, 1238 cm-1; MS (EI): m/z (%) 338 (7) [M]+, 271 (32), 184 (100), 131 (73), 103 (86), 70 (81), 56 (74), 44 (95). Anal. Calcd for C18 H18 N4 O3: C, 63.89; H, 5.36; N, 16.56. Found: C, 63.71; H, 5.47; N, 16.42.

7-Amino-1,3-diethyl-5-(4-fluorophenyl)-2,4-dioxo-1,3,4,5-tetrahydro-2H-pyrano[2,3-d]pyrimidine-6-carbonitrile (3j)

This compound was obtained from 1f an 2b; yield 1.60 g (90%); mp 159–162°C (lit [10] mp 160–162°C); 1H NMR: δ 1.01 (t, J = 7.3 Hz, 3H, CH3), 1.22 (t, J = 7.3 Hz, 3H, CH3), 3.65–3.83 (m, 2H, CH2), 3.88–4.05 (m, 2H, CH2), 4.35 (s, 1H, CH), 7.10 (t, J = 8.8 Hz, 2H, Ar), 7.21–7.31 (m, 2H, Ar) 7.34 (s, 2H, NH2).

7-Amino-5-(2-chlorophenyl)-1,3-diethyl-2,4-dioxo-1,3,4,5-tetrahydro-2H-pyrano[2,3-d]pyrimidine-6-carbonitrile (3k)

This compound was obtained from 1e and 2b; yield 1.71 g (92%); mp 185–187°C (lit [10] mp 186–187°C); 1H NMR: δ 1.00 (t, J = 6.8 Hz, 3H, CH3), 1.23 (t, J = 6.8 Hz, 3H, CH3), 3.71 (q, J = 6.8 Hz, 2H, CH2), 3.98 (q, J = 6.8 Hz, 2H, CH2), 4.84 (s, 1H, CH), 7.15–7.44 (m, 6H, Ar, NH2).


Corresponding author: Michail N. Elinson, N. D. Zelinsky Institute of Organic Chemistry, Leninsky Prospect 47, 119991 Moscow, Russia, e-mail:

Acknowledgments

The authors gratefully acknowledge the financial support of the Russian Foundation for Basic Research (Project No. 13-03-00096a).

Funding: Russian Foundation for Basic Research (Project No. 13-03-00096a).

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Received: 2014-7-2
Accepted: 2014-7-12
Published Online: 2014-8-12
Published in Print: 2014-10-1

©2014 by De Gruyter

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