An Efficient One-pot Two-component Protocol for Regio- and Chemoselective Synthesis of 5-Aryloyl-1,3,7,9-tetraalkyl-2,8-dithioxo-2,3,8,9-tetrahydro-1H-pyrano[2,3-d:6,5-d']dipyrimidine-4,6(5H,7H)-diones

Mehdi Rimaz; Hossein Rabiei; Behzad Khalili; Rolf H. Prager

doi:10.1071/CH13438

RESEARCH ARTICLE

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An Efficient One-pot Two-component Protocol for Regio- and Chemoselective Synthesis of 5-Aryloyl-1,3,7,9-tetraalkyl-2,8-dithioxo-2,3,8,9-tetrahydro-1H-pyrano[2,3-d:6,5-d']dipyrimidine-4,6(5H,7H)-diones

Mehdi Rimaz ^A ^D , Hossein Rabiei ^A , Behzad Khalili ^B and Rolf H. Prager ^C

+ Author Affiliations

- Author Affiliations

^A Department of Chemistry, Payame Noor University, PO Box 19395-3697, Tehran, Iran.

^B Department of Chemistry, Faculty of Sciences, University of Guilan, PO Box 41335-1914, Rasht, Iran.

^C School of Chemistry, Physics and Earth Sciences, Flinders University, Adelaide 5001, Australia.

^D Corresponding author. Email: rimaz.mehdi@gmail.com

Australian Journal of Chemistry 67(2) 283-288 https://doi.org/10.1071/CH13438
Submitted: 27 August 2013 Accepted: 8 October 2013 Published: 12 November 2013

Abstract

Novel symmetric fused pyrano[2,3-d]pyrimidine derivatives were synthesized in 75–92 % yield by a one-pot two-component reaction of arylglyoxals and 1,3-dialkyl-2-thiobarbituric acids in ethanol at room temperature. This is the first protocol to be reported for the synthesis of 5-aryloyl-1,3,7,9-tetraalkyl-2,8-dithioxo-2,3,8,9-tetrahydro-1H-pyrano[2,3-d:6,5-d′]dipyrimidine-4,6(5H,7H)-diones and the significant features of the present protocol are simplicity, high yields, a simple isolation procedure, and high chemoselectivity.

Introduction

Pyrane and its derivatives have attracted great interest owing to the incorporation of this ring system in compounds showing antimicrobial,^[¹^–³^] influenza inhibition, virus sialidase,^[⁴^] mutagenic,^[⁵^] antiviral,^[⁶^] antiproliferation,^[⁷^] sex-pheromone,^[⁸^] antitumour,^[⁹^] and anti-inflammatory activity.^[¹⁰^] Moreover, pyrane derivatives are well known for their antihistaminic activity.^[¹¹^] Also, pyrimidines and their fused derivatives play an essential role in several biological processes of chemical and pharmacological importance. In particular, the pyrimidine nucleus can be found in a broad variety of antibacterial, antiviral, NAR (nicotinic acid receptor), and antitumour agents as well as in agrochemical and veterinary products.^[¹²^–¹⁵^] Examples of such compounds are emivirine and 5-ethyl-2-thioxo-2,3-dihydro-1H-pyrano[2,3-d]pyrimidine pyrano[2,3-d]pyrimidine-4,7-dione (Fig. 1.).^[¹⁶^,¹⁷^]

**Fig. 1.** Structure of two biologically active pyrimidine derivatives.

Designing new multicomponent reactions (MCRs) as well as improving known MCRs constitutes a research area of immense interest in contemporary organic synthesis.^[¹⁸^] In contrast to classical multistep linear synthetic protocols, MCRs enable expedient and efficient assembly of molecules of structural complexity and diversity in one-pot operations with facile execution, and high atom economy and selectivity.^[^18b^,^18c^,¹⁹^,²⁰^] These reactions obviate the isolation and purification of intermediates and diminish waste generation, thereby enhancing the greenness of transformations. Consequently, MCRs have emerged as a powerful tool for delivering molecular libraries needed in combinatorial approaches for the assembly and lead identification of bioactive compounds.^[²¹^]

Based on the above considerations and in continuance of our previous research into the arylglyoxal-mediated synthesis of various heterocycles,^[²²^–³²^] we have found that 1,3-dialkyl thiobarbituric acids undergo a tandem Knoevenagel–Michael condensation with arylglyoxals leading to the formation of a substituted pyranopyrimidine skeleton. Herein, we report an efficient two-component strategy for synthesis of symmetrically substituted 5-aryloyl-1H-pyrano[2,3-d]pyrimidine 1. The retrosynthesis of this novel strategy is shown in Scheme 1.

**Scheme 1.** Retrosynthesis of substituted 5-aryloyl-1H-pyrano[2,3-d]pyrimidine.

Results and Discussion

During our recent work on the synthesis of new pyrimidopyridazine derivatives,^[²²^] we found that in some cases stirring the mixture of 1,3-diethyl-2-thiobarbituric acid or 1,3-dimethyl-2-thiobarbituric acid and arylglyoxals with hydrazine in ethanol at room temperature led to the formation of insoluble intermediates that did not react with the hydrazine. We have now investigated these reactions in the absence of hydrazine and have characterized the products as previously unreported pyranopyrimidine derivatives.

The arylglyoxal derivatives (2a–j) react with two equivalents of 1,3-diethyl-2-thiobarbituric acid (3a) or 1,3-dimethyl-2-thiobarbituric acid (3b) in ethanol at room temperature to produce symmetric pyrano[2,3-d]pyrimidine derivatives 1a–s that partially exist as the enol tautomers 4a–s in solution (Scheme 2, Table 1).

**Scheme 2.** Synthesis of substituted pyranopyrimidine derivatives.

**Table 1. Pyranopyrimidines prepared according to Scheme 2**

The reactions proceeded to completion in 2–3 h, and the pure products were obtained simply by recrystallization from methanol; no chromatographic purification was necessary. As mentioned above, the enol forms exist only in solution and all compounds were obtained as keto forms from the reaction mixture. Notably, there is no signal for the OH group in Fourier-transform (FT)IR spectra because these spectra were recorded in the solid state. The keto/enol ratio was ~1 : 1 in all cases in chloroform, except with the strongly electron withdrawing nitro substituent in 1o, where none of the enol tautomer could be detected. However, when the N-alkyl group was changed from methyl to ethyl, as in 1e, the general 1 : 1 keto/enol ratio in solution was restored. The novel compounds listed in Table 1 were characterized by IR, ¹H NMR and ¹³C NMR spectra, and elemental analyses.

As shown in Table 1, all the obtained pyranopyrimidine derivatives exist as mixtures of keto and enol tautomers in solution. In the ¹H NMR spectra of the products, the OH group of the enol tautomer shows a broad singlet at δ 8.21–13.18 ppm, and in keto tautomers, the α CH adjacent to the carbonyl of the aryloyl group shows a sharp singlet at δ 4.91–5.69 ppm, which was used to calculate the keto/enol ratio.

As suggested in Scheme 3, the formation of the product involves the initial regioselective formation of a Knoevenagel adduct 6 by condensation between 2 and 5, followed by regioselective Michael addition between 6 and 5 to give the intermediate 7, dehydration of which leads to the formation of products 1a–s, and their enol tautomers 4a–s.

**Scheme 3.** Proposed mechanism for regio- and chemoselective formation of substituted pyrano[2,3-d]pyrimidines.

As noted in our previous work, the initial attack of the 1,3-dialkyl-2-thiobarbituric acid occurred exclusively on the formyl group of the arylglyoxal and subsequent Michael addition also occurred regioselectively and chemoselectively.

The possible utility of the products described in the present paper is enhanced by noting that the high enol content of the products in solution allows their facile alkylation on carbon or oxygen, allowing modification of their shape or transport properties. This aspect of the work is being actively pursued.

Conclusion

In summary, we have developed an efficient high-yielding protocol for the regio- and chemoselective synthesis of substituted symmetric pyrano[2,3-d]pyrimidines that does not require any catalyst. The protocol involves a two-component reaction of arylglyoxals with 1,3-dialkyl-2 thiobarbituric acids in ethanol at room temperature, leading to chemoselective synthesis of 5-aryloyl-1,3,7,9-tetraalkyl-2,8-dithioxo-2,3,8,9-tetrahydro-1H-pyrano[2,3-d:6,5-d′]dipyrimidine-4,6(5H,7H)-diones. The advantages offered by this strategy are: simple operation, mild reaction conditions, ease of product isolation, and good to excellent yields.

Experimental

General Procedures

Arylglyoxals and 1,3-dimethyl-2-thiobarbituric acid were prepared by reported procedures.^[³³^,³⁴^] Other starting materials and solvents were obtained from Merck (Germany) and Fluka (Switzerland) and were used without further purification. The methods used to monitor the reactions were TLC and NMR. Melting points were measured on an Electrothermal 9200 apparatus. IR spectra were obtained on a Nexus-670 FTIR spectrometer. ¹H and ¹³C NMR spectra (CDCl₃) were recorded on a Bruker DRX-300 Avance spectrometer at 300 and 75.5 MHz respectively. Elemental analyses were performed using a Leco Analyzer 932.

General Procedure for the Synthesis of 5-Aryloyl-1,3,7,9-tetraalkyl-2,8-dithioxo-2,3,8,9-tetrahydro-1H-pyrano[2,3-d:6,5-d']dipyrimidine-4,6(5H,7H)-diones

A mixture of 1,3-diethyl (or dimethyl)-2-thiobarbituric acid (1 mmol) and arylglyoxal (1 mmol) in absolute ethanol (10 mL) was stirred at room temperature for 2–3 h. After the appropriate time, the resulting precipitate was filtered and washed with ethanol. The crude products were recrystallized from methanol.

5-Benzoyl-1,3,7,9-tetraethyl-2,8-dithioxo-2,3,8,9-tetrahydro-1H-pyrano[2,3-d:6,5-d']dipyrimidine-4,6(5H,7H)-dione 1a

Cream powder, 79 %, mp 197°C (dec.). δ_H 1.12 (t, J 6.9, 6H, 2 × CH₃), 1.36 (t, J 6.9, 6H, 2 × CH₃), 4.49 (q, J 6.9, 4H, 2 × CH₂), 4.62 (q, J 6.9, 4H, 2 × CH₂), 5.57 (s, 1H, CH in keto tautomer), 7.37 (t, J 7.5, 2H, Ar), 7.49 (t, J 7.5, 1H, Ar), 7.67 (d, J 7.5, 2H, Ar), 10.06 (bs, 1H, OH in enol tautomer). δ_C 11.6, 12.0, 41.5, 44.5, 44.9, 95.9, 127.6, 128.2, 132.7, 136.0, 162.3, 162.9, 174.5, 194.4. ν_max (KBr)/cm^–1 2981, 2935, 2520, 1694, 1622, 1444, 1384, 1269, 1110, 785. Anal. Calc. for C₂₄H₂₆N₄O₄S₂: C 57.81, H 5.26, N 11.24, S 12.86. Found: C 57.90, H 5.29, N 11.30, S 12.90 %.

5-(4-Bromobenzoyl)-1,3,7,9-tetraethyl-2,8-dithioxo-2,3,8,9-tetrahydro-1H-pyrano[2,3-d:6,5-d']dipyrimidine-4,6(5H,7H)-dione 1b

Pink powder, 81 %, mp 193°C (dec.). δ_H 1.15 (t, J 6.9, 6H, 2 × CH₃), 1.35 (t, J 6.9, 6H, 2 × CH₃), 4.50 (q, J 6.3, 4H, 2 × CH₂), 4.61 (q, J 6.3, 4H, 2 × CH₂), 5.52 (s, 1H, CH in keto tautomer), 7.57–7.48 (m, 4H, Ar), 11.58 (bs, 1H, OH in enol tautomer). δ_C 11.6, 12.0, 41.4, 44.6, 45.0, 95.6, 127.7, 129.1, 131.5, 134.8, 162.4, 162.9, 174.4, 193.4. ν_max (KBr)/cm^–1 2981, 2934, 2521, 1700, 1621, 1585, 1437, 1383, 1269, 1110, 798. Anal. Calc. for C₂₄H₂₅BrN₄O₄S₂: C 49.91, H 4.36, N 9.70, S 11.10. Found: C 49.84, H 3.31, N 9.88, S 11.14 %.

5-(4-Chlorobenzoyl)-1,3,7,9-tetraethyl-2,8-dithioxo-2,3,8,9-tetrahydro-1H-pyrano[2,3-d:6,5-d']dipyrimidine-4,6(5H,7H)-dione 1c

Yellow powder, 85 %, mp 202°C (dec.). δ_H 1.16 (t, J 6.3, 6H, 2 × CH₃), 1.33 (t, J 6.3, 6H, 2 × CH₃), 4.51 (q, J 6.3, 4H, 2 × CH₂), 4.62 (q, J 6.3, 4H, 2 × CH₂), 5.53 (s, 1H, CH in keto tautomer), 7.36 (d, J 8.4, 2H, Ar), 7.63 (d, J 8.1, 2H, Ar), 9.47 (bs, 1H, OH in enol tautomer). δ_C 11.6, 12.0, 41.4, 44.6, 45.0, 95.7, 128.6, 129.0, 134.3, 139.1, 162.4, 162.9, 174.4, 193.2. ν_max (KBr)/cm^–1 2982, 2935, 2875, 2516, 1699, 1621, 1435. Anal. Calc. for C₂₄H₂₅ClN₄O₄S₂: C 54.08, H 4.73, N 10.51, S 12.03. Found: C 54.12, H 4.70, N 10.60, S 12.10 %.

5-(4-Fluorobenzoyl)-1,3,7,9-tetraethyl-2,8-dithioxo-2,3,8,9-tetrahydro-1H-pyrano[2,3-d:6,5-d']dipyrimidine-4,6(5H,7H)-dione 1d

Pink powder, 80 %, mp 204°C (dec.). δ_H 1.15 (bt, J 6.9, 6H, 2 × CH₃), 1.35 (bt, J 6.3, 6H, 2 × CH₃), 4.50 (q, J 6.3, 4H, 2 × CH₂), 4.62 (q, J 6.3, 4H, 2 × CH₂), 5.54 (s, 1H, CH in keto tautomer), 7.08–7.02 (m, 2H, Ar), 7.73–7.69 (m, 2H, Ar), 9.78 (bs, 1H, OH in enol tautomer). δ_C 11.6, 12.0, 41.4, 44.6, 45.0, 95.8, 115.3, 115.6, 130.2, 130.3, 132.2, 162.4, 162.9, 163.5, 166.9, 174.4, 192.8. ν_max (KBr)/cm^–1 3075, 2984, 2520, 1698, 1623, 1597, 1440, 1383, 1269, 1110, 849, 783. Anal. Calc. for C₂₄H₂₅FN₄O₄S₂: C 55.80, H 4.88, N 10.85, S 12.41. Found: C 55.78, H 4.89, N 10.96, S 12.50 %.

5-(4-Nitrobenzoyl)-1,3,7,9-tetraethyl-2,8-dithioxo-2,3,8,9-tetrahydro-1H-pyrano[2,3-d:6,5-d']dipyrimidine-4,6(5H,7H)-dione 1e

Grey powder, 88 %, mp 223°C (dec.). δ_H 1.15 (t, J 6.6, 6H, 2 × CH₃), 1.36 (t, J 6.6, 6H, 2 × CH₃), 4.49 (q, J 6.6, 4H, 2 × CH₂), 4.62 (q, J 6.6, 4H, 2 × CH₂), 5.58 (s, 1H, CH in keto tautomer), 7.76 (d, J 8.7, 2H, Ar in enol tautomer), 7.84 (d, J 8.7, 2H, Ar in keto tautomer), 8.25 (d, J 8.7, 2H, Ar in keto tautomer), 8.28 (d, J 8.7, 2H, Ar in enol tautomer), 9.92 (bs, 1H, OH in enol tautomer). δ_C 11.6, 11.9, 41.8, 44.6, 44.9, 95.1, 123.4, 125,6, 128.6, 141.4, 149.8, 161.5, 162.3, 163.0, 174.4, 193.2. ν_max (KBr)/cm^–1 3078, 2976, 2934, 2521, 1709, 1619, 1528, 1430, 1382, 1271, 1110, 857, 798. Anal. Calc. for C₂₄H₂₅N₅O₆S₂: C 53.03, H 4.64, N 12.88, S 11.80. Found: C 53.00, H 4.68, N 13.01, S 11.83 %.

5-(4-Methoxybenzoyl)-1,3,7,9-tetraethyl-2,8-dithioxo-2,3,8,9-tetrahydro-1H-pyrano[2,3-d:6,5-d']dipyrimidine-4,6(5H,7H)-dione 1f

Pink powder, 82 %, mp 202°C (dec.). δ_H 1.52–1.02 (m, 12H, 4 × CH₃), 3.84 (s, 3H, OCH₃), 4.77–4.27 (m, 8H, 4 × CH₂), 5.55 (s, 1H, CH in keto tautomer), 6.85 (d, J 8.7, 2H, Ar), 7.69 (d, J 8.7, 2H, Ar), 9.44 (bs, 1H, OH in enol tautomer). δ_C 11.6, 12.0, 41.5, 44.5, 45.0, 55.4, 96.0, 112.5, 119.3, 119.9, 129.1, 137.2, 159.4, 162.4, 162.8, 174.4, 194.1. ν_max (KBr)/cm^–1 2981, 2935, 2521, 1688, 1620, 1437, 1383, 1263, 1109, 780. Anal. Calc. for C₂₅H₂₈N₄O₅S₂: C 56.80, H 5.34, N 10.60, S 12.13. Found: C 56.84, H 5.36, N 10.69, S 12.18 %.

5-(3-Bromobenzoyl)-1,3,7,9-tetraethyl-2,8-dithioxo-2,3,8,9-tetrahydro-1H-pyrano[2,3-d:6,5-d']dipyrimidine-4,6(5H,7H)-dione 1g

Pink powder, 75 %, mp 179°C (dec.). δ_H 1.18 (t, J 6.9, 6H, 2 × CH₃), 1.37 (t, J 6.9, 6H, 2 × CH₃), 3.91 (q, J 6.9, 4H, 2 × CH₂), 3.94 (q, J 6.9, 4H, 2 × CH₂), 5.59 (s, 1H, CH in keto tautomer), 7.03 (d, J 6.9, 1H, Ar), 7.32–7.25 (m, 3H, Ar), 11.63 (bs, 1H, OH in enol tautomer). δ_C 11.6, 12.0, 41.6, 44.6, 45.0, 95.6, 122.4, 125.9, 129.7, 130.9, 135.5, 137.8, 162.3, 162.9, 174.5, 193.0. ν_max (KBr)/cm^–1 2955, 2878, 2559, 1708, 1633, 1592, 1459, 1375, 1110, 878, 795. Anal. Calc. for C₂₄H₂₅BrN₄O₄S₂: C 49.91, H 4.36, N 9.70, S 11.10. Found: C 49.93, H 4.37, N 9.81, S 11.17 %.

5-(3-Methoxybenzoyl)-1,3,7,9-tetraethyl-2,8-dithioxo-2,3,8,9-tetrahydro-1H-pyrano[2,3-d:6,5-d']dipyrimidine-4,6(5H,7H)-dione 1h

White powder, 77 %, mp 179°C (dec.). δ_H 1.15 (t, J 6.3, 6H, 2 × CH₃), 1.35 (t, J 6.3, 6H, 2 × CH₃), 3.81 (s, 3H, OCH₃), 4.51 (q, J 6.3, 4H, 2 × CH₂), 4.61 (q, J 6.3, 4H, 2 × CH₂), 5.56 (s, 1H, CH in keto tautomer), 7.04 (d, J 7.8, 1H, Ar in enol tautomer), 7.30–7.18 (m, 3H, Ar), 10.95 (bs, 1H, OH in enol tautomer). δ_C 11.6, 12.0, 41.5, 44.6, 45.0, 55.4, 96.0, 112.5, 119.3, 119.9, 129.1, 137.2, 159.4, 162.4, 162.8, 174.5, 194.1. ν_max (KBr)/cm^–1 2979, 2934, 2523, 1702, 1621, 1445, 1380, 1269, 1110, 790. Anal. Calc. for C₂₅H₂₈N₄O₅S₂: C 56.80, H 5.34, N 10.60, S 12.13. Found: C 56.79, H 5.39, N 10.71, S 12.16 %.

5-(3,4-Dimethoxybenzoyl)-1,3,7,9-tetraethyl-2,8-dithioxo-2,3,8,9-tetrahydro-1H-pyrano[2,3-d:6,5-d']dipyrimidine-4,6(5H,7H)-dione 1i

Grey powder, 84 %, mp 201°C (dec.). δ_H 1.47–0.90 (m, 12H, 4 × CH₃), 3.87 (s, 3H, OCH₃), 3.90 (s, 3H, OCH₃), 4.72–4.33 (m, 8H, 4 × CH₂), 5.57 (s, 1H, CH in keto tautomer), 6.77 (d, J 8.4, 1H, Ar in),7.26 (d, J 8.4, 1H, Ar in enol tautomer), 7.34 (s, 1H, Ar), 12.01 (bs, 1H, OH in enol tautomer). δ_C 11.9, 41.4, 44.3, 44.7, 55.9, 56.0, 96.3, 109.8, 110.8, 121.7, 128.4, 148.7, 153.0, 162.6, 174.4, 192.6. ν_max (KBr)/cm^–1 2987, 2898, 2542, 1692, 1623, 1561, 1472, 1385, 1270, 1112, 771. Anal. Calc. for C₂₆H₃₀N₄O₆S₂: C 55.90, H 5.41, N 10.03, S 11.48. Found: C 55.95, H 4.44, N 10.10, S 11.53 %.

5-(3,4-Methylenedioxybenzoyl)-1,3,7,9-tetraethyl-2,8-dithioxo-2,3,8,9-tetrahydro-1H-pyrano[2,3-d:6,5-d']dipyrimidine-4,6(5H,7H)-dione 1j

Pink powder, 83 %, mp 161°C (dec.). δ_H (CDCl₃, 300 MHz) 1.23 (t, J 7.5, 6H, 2 × CH₃), 1.34 (t, J 7.5, 6H, 2 × CH₃), 4.71–4.29 (m, 8H, 4 × CH₂), 5.53 (s, 1H, CH in keto tautomer), 6.03 (s, 2H, CH₂), 6.76 (d, J 8.1, 1H, Ar in), 7.26–7.14 (m, 2H, Ar), 7.34 (s, 1H, Ar), 8.21 (bs, 1H, OH in enol tautomer). δ_C 11.8, 11.9, 44.7, 44.8, 96.1, 101.8, 123.4, 130.1, 147.8, 151.5, 163.1, 174.5, 192.4. ν_max (KBr)/cm^–1 2982, 2935, 2527, 1701, 1620, 1440, 1383, 1269, 1250, 1110, 1038, 793, 731. Anal. Calc. for C₂₅H₂₆N₄O₆S₂: C 55.34, H 4.83, N 10.33, S 11.82. Found: C 55.31, H 4.81, N 10.45, S 11.88 %.

5-Benzoyl-1,3,7,9-tetramethyl-2,8-dithioxo-2,3,8,9-tetrahydro-1H-pyrano[2,3-d:6,5-d']dipyrimidine-4,6(5H,7H)-dione 1k

Cream powder, 83 %, mp 202°C (dec.) δ_H (CDCl₃, 300 MHz) 3.84–3.58 (m, 12H, 4 × CH₃), 5.69 (s, 1H, CH in keto tautomer), 7.40 (t, J 7.5, 2H, Ar), 7.53 (t, J 7.5, 1H, Ar), 7.73 (d, J 7.5, 2H, Ar), 8.55 (bs, 1H, OH in enol tautomer). δ_C 35.3, 36.6, 41.5, 95.9, 127.8, 128.5, 133.0, 135.7, 162.8, 163.2, 175.4, 194.2. ν_max (KBr)/cm^–1 2952, 2869, 2484, 1702, 1621, 1467, 1394, 1339, 1295, 1339, 1110, 789. Anal. Calc. for C₂₄H₂₆N₄O₄S₂: C 57.81, H 5.26, N 11.24, S 12.86. Found: C 57.90, H 5.29, N 11.30, S 12.90 %.

5-(4-Bromobenzoyl)-1,3,7,9-tetramethyl-2,8-dithioxo-2,3,8,9-tetrahydro-1H-pyrano[2,3-d:6,5-d']dipyrimidine-4,6(5H,7H)-dione 1l

Pink powder, 87 %, mp 237°C (dec.). δ_H 3.62 (s, 6H, 2 × CH₃), 3.84 (s, 6H, 2 × CH₃), 5.63 (s, 1H, CH in keto tautomer), 7.55 (d, J 8.4, 2H, Ar), 7.61 (d, J 8.1, 2H, Ar), 9.49 (bs, 1H, OH in enol tautomer). δ_C 36.4, 36.6, 41.5, 95.7, 128.1, 129.3, 131.9, 134.5, 162.7, 163.2, 175.4, 193.2. ν_max (KBr)/cm^–1 2947, 2556, 1706, 1619, 1586, 1461, 1391, 1342, 1111, 810. Anal. Calc. for C₂₀H₁₇BrN₄O₄S₂: C 46.07, H 3.29, N 10.75, S 12.30. Found: C 46.10, H 3.31, N 10.66, S 12.35 %.

5-(4-Chlorobenzoyl)-1,3,7,9-tetramethyl-2,8-dithioxo-2,3,8,9-tetrahydro-1H-pyrano[2,3-d:6,5-d']dipyrimidine-4,6(5H,7H)-dione 1m

Yellow powder, 86 %, mp 227°C (dec.). δ_H 3.71 (s, 6H, 2 × CH₃), 3.82 (s, 6H, 2 × CH₃), 5.63 (s, 1H, CH in keto tautomer), 7.46 (d, J 6.9, 2H, Ar), 7.67 (d, J 6.9, 2H, Ar), 8.58 (bs, 1H, OH in enol tautomer). δ_C 36.9, 37.1, 41.7, 96.3, 128.7, 129.8, 132.8, 135.1, 161.6, 163.1, 177.3, 192.8. ν_max (KBr)/cm^–1 2951, 2932, 2551, 1708, 1620, 1590, 1465, 1387, 1226, 1110, 790. Anal. Calc. for C₂₀H₁₇ClN₄O₄S₂: C 50.36, H 3.59, N 11.75, S 13.45. Found: C 50.32, H 3.57, N 11.60, S 13.50 %.

5-(4-Fluorobenzoyl)-1,3,7,9-tetramethyl-2,8-dithioxo-2,3,8,9-tetrahydro-1H-pyrano[2,3-d:6,5-d']dipyrimidine-4,6(5H,7H)-dione 1n

Pink powder, 84 %, mp 210°C (dec.). δ_H 3.72 (s, 6H, 2 × CH₃), 3.83 (s, 6H, 2 × CH₃), 5.65 (s, 1H, CH in keto tautomer), 7.11–7.05 (m, 2H, Ar), 7.79–7.75 (m, 2H, Ar), 11.21 (bs, 1H, OH in enol tautomer). δ_C 36.6, 41.5, 95.8, 115.6, 115.9, 130.4, 130.5, 131.9, 132.0, 162.7, 163.1, 163.7, 167.1, 175.4, 192.6. ν_max (KBr)/cm^–1 3069, 2981, 2538, 1692, 1618, 1588, 1472, 1381, 1264, 856, 778. Anal. Calc. for C₂₀H₁₇FN₄O₄S₂: C 52.16, H 3.72, N 12.17, S 13.93. Found: C 52.14, H 3.75, N 12.01, S 13.97 %.

5-(4-Nitrobenzoyl)-1,3,7,9-tetramethyl-2,8-dithioxo-2,3,8,9-tetrahydro-1H-pyrano[2,3-d:6,5-d']dipyrimidine-4,6(5H,7H)-dione 1o

Beige powder, 92 %, mp 228°C (dec.). δ_H 3.70 (s, 6H, 2 × CH₃), 3.85 (s, 6H, 2 × CH₃), 5.69 (s, 1H, CH in keto tautomer), 7.89 (d, J 8.7, 2H, Ar in keto tautomer), 8.27 (d, J 8.7, 2H, Ar in keto tautomer). δ_C 36.4, 36.7, 42.0, 95.1, 123.7, 124.6, 128.7, 141.0, 150.1, 162.7, 175.4, 202.5. ν_max (KBr)/cm^–1 2951, 2541, 1713, 1621, 1526, 1394, 1345, 1109, 789. Anal. Calc. for C₂₀H₁₇N₅O₆S₂: C 49.27, H 3.51, N 14.37, S 13.15. Found: C 49.30, H 3.55, N 14.30, S 13.19 %.

5-(4-Methoxybenzoyl)-1,3,7,9-tetramethyl-2,8-dithioxo-2,3,8,9-tetrahydro-1H-pyrano[2,3-d:6,5-d']dipyrimidine-4,6(5H,7H)-dione 1p

Pink powder, 87 %, mp 201°C (dec.). δ_H 3.14 (s, 6H, 2 × CH₃), 3.16 (s, 6H, 2 × CH₃), 3.83 (s, 3H, OCH₃), 4.91 (s, 1H, CH of keto tautomer), 6.87 (d, J 8.4Hz, 2H, Ar), 7.32 (d, J 8.1Hz, 2H, Ar), 9.49 (s, 1H, OH in enol tautomer). δ_C 36.6, 41.3, 55.4, 96.1, 113.8, 114.2, 128.1, 130.2, 131.0, 162.8, 163.5, 175.4, 192.8. ν_max (KBr)/cm^–1 2947, 2560, 1691, 1595, 1466, 1395, 1338, 1171, 1110, 1023, 787. Anal. Calc. for C₂₁H₂₀N₄O₅S₂: C 53.38, H 4.27, N 11.86, S 13.57. Found: C 53.41, H 4.25, N 11.77, S 13.61 %.

5-(3-Bromobenzoyl)-1,3,7,9-tetramethyl-2,8-dithioxo-2,3,8,9-tetrahydro-1H-pyrano[2,3-d:6,5-d']dipyrimidine-4,6(5H,7H)-dione 1q

Pink powder, 79 %, mp 152°C (dec.). δ_H 3.72 (s, 6H, 2 × CH₃), 3.82 (s, 6H, 2 × CH₃), 5.67 (s, 1H, CH in keto tautomer), 7.06 (d, J 5.4, 1H, Ar), 7.32–7.25 (m, 3H, Ar), 13.18 (bs, 1H, OH in enol tautomer). δ_C 36.7, 41.6, 96.0, 112.8, 119.5, 119.9, 129.7, 136.9, 159.6, 162.7, 175.4, 193.9. ν_max (KBr)/cm^–1 2941, 2548, 1700, 1625, 1579, 1470, 1365, 1111, 875, 790. Anal. Calc. for C₂₀H₁₇BrN₄O₄S₂: C 46.07, H 3.29, N 10.75, S 12.30. Found: C 46.12, H 3.32, N 10.68, S 12.39 %.

5-(3-Methoxybenzoyl)-1,3,7,9-tetramethyl-2,8-dithioxo-2,3,8,9-tetrahydro-1H-pyrano[2,3-d:6,5-d']dipyrimidine-4,6(5H,7H)-dione 1r

Pink powder, 80 %, mp 187°C (dec.). δ_H 3.72 (s, 3H, OCH₃), 3.83 (s, 12H, 2 × CH₃), 5.68 (s, 1H, CH in keto tautomer), 7.32–7.26 (m, 3H, Ar), 7.70 (d, J 7.5, 1H, Ar), 9.38 (bs, 1H, OH in enol tautomer). δ_C 36.5, 41.6, 55.3, 96.0, 112.7, 119.5, 119.9, 129.4, 136.9, 159.6, 163.0, 175.4, 193.9. ν_max (KBr)/cm^–1 2946, 2557, 1697, 1607, 1455, 1340, 1168, 1110, 1025, 752. Anal. Calc. for C₂₁H₂₀N₄O₅S₂: C 53.38, H 4.27, N 11.86, S 13.57. Found: C 53.37, H 4.24, N 11.83, S 13.60 %.

5-(3,4-Dimethoxybenzoyl)-1,3,7,9-tetramethyl-2,8-dithioxo-2,3,8,9-tetrahydro-1H-pyrano[2,3-d:6,5-d']dipyrimidine-4,6(5H,7H)-dione 1s

Grey powder, 82 %, mp 207°C (dec.). δ_H 3.67 (s, 6H, 2 × CH₃), 3.79 (s, 6H, 2 × CH₃), 3.90 (s, 3H, OCH₃), 3.93 (s, 3H, OCH₃), 5.70 (s, 1H, CH in keto tautomer), 6.80 (d, J 8.4, 1H, Ar), 7.30 (d, J 8.7, 1H, Ar), 7.44 (s, 1H, Ar), 8.90 (bs, 1H, OH in enol tautomer). δ_C 36.6, 41.2, 55.9, 56.0, 96.3, 110.9, 121.9, 128.1, 149.0, 153.3, 162.8, 175.4, 192.7. ν_max (KBr)/cm^–1 3001, 2932, 2874, 2834, 2529, 1696, 1618, 1516, 1465, 1338, 1265, 1111, 1026, 790. Anal. Calc. for C₂₂H₂₂N₄O₆S₂: C 52.58, H 4.41, N 11.15, S 12.76. Found: C 52.55, H 4.40, N 11.10, S 12.85 %.

Supplementary Material

IR, ¹H NMR and ¹³C NMR spectra of pyranopyrimidine derivatives are available on the Journal’s website.

Acknowledgements

Financial support from the Research Council of Payame Noor University is gratefully acknowledged.

References

[1] A. M. El-Agrody, M. S. Abd El-Latif, N. A. El-Hady, A. H. Fakery, A. H. Bedair, Molecules 2001, 6, 519.
| Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD3MXntleisrs%3D&md5=3633fb6c845bc050538612dd37adbfa6CAS |

[2] A. H. Bedair, N. A. El-Hady, M. S. Abd El-Latif, A. H. Fakery, A. M. El-Agrody, lL Farmaco 2000, 55, 708.
| Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD3MXis1Ojug%3D%3D&md5=30e18e07fc49c28307fba12c61ed170aCAS |

[3] A. M. El-Agrody, M. H. El-Hakim, M. S. Abd El-Latif, A. H. Fakery, E. M. El-Sayed, K. A. El-Ghareab, Acta Pharm. 2000, 50, 111.
| 1:CAS:528:DC%2BD3cXlsFOktLw%3D&md5=9a36cd25c4bf2c652add5af0c85ec962CAS |

[4] R. N. Taylor, A. Cleasby, O. Singh, T. Skarzynski, J. Med. Chem. 1998, 41, 798.
| Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaK1cXhtF2murY%3D&md5=e09088cde1afa555d5b49652f2adc7c5CAS |

[5] K. Hiramoto, A. Nasuhara, K. Michiloshi, T. Kato, K. Kikugawa, Mutat. Res. 1997, 395, 47.
| Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaK1cXisl2htA%3D%3D&md5=2e85076febb28f9ecca392ec39cd0d10CAS | 9465913PubMed |

[6] A. Martinez-Grau, L. J. Marco, Bioorg. Med. Chem. Lett. 1997, 7, 3165.
| Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaK1cXjtVGjtQ%3D%3D&md5=93cbe9eb33dbea1f0257965025e51773CAS |

[7] C. P. Dell, C. W. Smith, Chem. Abstr. 1993, 119, 139102d.

[8] G. Bianchi, A. Tava, Agric. Biol. Chem. 1987, 51, 2001.
| Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaL1cXhs1Oitrw%3D&md5=c1af1394041eff1a78413d2154962311CAS |

[9] F. Eiden, F. Denk, Arch. Pharm. 1991, 324, 353.
| Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaK3MXkvFaisLw%3D&md5=656af1bae14801478fd2eff5603a881bCAS |

[10] C. J. Shishoo, M. B. Devani, G. V. Ullas, S. Ananthan, V. S. Bahadit, J. Heterocycl. Chem. 1981, 18, 43.
| Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaL3MXkt1Cqtb4%3D&md5=bedf3c7e75aa4a104d47f02baa25029fCAS |

[11] K. Noda, A. Nakagawa, Y. Nakajima, H. Ide, Chem. Abstr. 1978, 88, 50908q.

[12] Z. H. Ismail, M. M. Ghorab, E. M. A. Mohamed, H. M. Aly, M. S. A. El-Gaby, Phosphorus Sulfur Silicon Relat Elem. 2008, 183, 2541.
| Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD1cXhtFKlsr3K&md5=6ede2393b08eea374d0463ae47b73185CAS |

[13] S. A. El-Gaby, S. M. Abdel-Gawad, M. M. Ghorab, H. I. Heiba, H. M. Aly, Phosphorus Sulfur Silicon Relat. Elem. 2006, 181, 279.
| Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD28XmslSq&md5=301536da6e5dd9f99a8affdc623f4884CAS |

[14] L. P. Prikazchikova, B. M. Khutova, I. F. Vladimirtsev, I. V. Boldyrev, N. I. Zhuravskaya, Chem. Abstr. 1975, 83, 127346m.

[15] D. Brown, A. R. Katritzky, C. W. Rees, Comprehensive Heterocyclic Chemistry, 1984, 3, p. 443 (Pergamon Press: Oxford).

[16] M. Bollini, R. A. Domaoal, V. V. Thakur, R. G. Macias, K. A. Spasov, K. S. Anderson, W. L. Jorgensen, J. Med. Chem. 2011, 54, 8582.
| Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC3MXhsVGkt7rE&md5=f71f02e9088da1b7e39dafea968a7374CAS | 22081993PubMed |

[17] X. Huang, J. Su, A. U. Rao, H. Tang, W. Zhou, X. Zhu, X. Chen, Z. Liu, Y. Huang, S. Degrado, D. Xiao, J. Qin, R. Aslanian, B. A. McKittrick, S. Greenfeder, M. V. Heek, M. Chintala, A. Palani, Bioorg. Med. Chem. Lett. 2012, 22, 854.
| Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC38XpsFejuw%3D%3D&md5=26d39060589ee08424a9a72ec42a9db2CAS | 22209457PubMed |

[18] (a) A. Domling, I. Ugi, Angew. Chem. Int. Ed. 2000, 39, 3168.
         | 1:CAS:528:DC%2BD3cXntleksbk%3D&md5=6b635319ca63db215939c0c19f9a45bdCAS |
         (b) J. Zhu, H. Bienayme, Multicomponent Reactions 2005 (Wiley-VCH: Weinheim).
      (c) A. Domling, Chem. Rev. 2006, 106, 17.

[19] (a) I. Ugi, Pure Appl. Chem. 2001, 73, 187.
         | Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD3MXjtVeksb8%3D&md5=2b798f220854a093717b05365f7e69bdCAS |
      (b) R. R. Nagawade, D. B. Shinde, Acta Chim. Slov. 2007, 54, 642.
      (c) D. M. D’Souza, T. Mueller, Chem. Soc. Rev. 2007, 36, 3169.
      (d) C. C. A. Cariou, G. J. Clarkson, M. Shipman, J. Org. Chem. 2008, 73, 9762.
         | Crossref | GoogleScholarGoogle Scholar |

[20]    (a) W. Bannwarth, E. Felder, Combinatorial Chemistry 2000 (Wiley-VCH: Weinheim).
      (b) G. Balme, E. Bossharth, N. Monteiro, Eur. J. Org. Chem. 2003, 4101.
         | Crossref | GoogleScholarGoogle Scholar |
      (c) R. V. A. Orru, M. De Greef, Synthesis 2003, 1471.
         | Crossref | GoogleScholarGoogle Scholar |
      (d) H. Bienaymé, C. Hulme, G. Oddon, P. Schmitt, Chem. Eur. J. 2000, 6, 3321.
         | Crossref | GoogleScholarGoogle Scholar |
      (e) G. Vasuki, K. Kumaravel, Tetrahedron Lett. 2008, 49, 5636.
         | Crossref | GoogleScholarGoogle Scholar |

[22] J. Khalafy, M. Rimaz, H. Rabiei, L. Panahi, J. Sulfur Chem. 2013, 34, 395.
| Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC38XhslektLvI&md5=1af24739aa167048b87c259adde7eb2eCAS |

[23] B. Khalili, F. S. Darabi, B. Eftekhari-sis, M. Rimaz, Monatsh. Chem. 2013, 144, 1569.
| Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC3sXhtV2rt73L&md5=e74f2c32c5f8401ab405052a7ded5972CAS |

[24] J. Khalafy, M. Rimaz, S. Farajzadeh, M. Ezzati, S. Afr. J. Chem. 2013, 66, 176.

[25] J. Khalafy, M. Rimaz, M. Ezzati, A. P. Marjani, Curr. Chem. Lett. 2013, 2, 43.
| Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC3sXhs1Ohsbc%3D&md5=bc51f24bfbc0393753e036e721526fafCAS |

[26] J. Khalafy, M. Rimaz, M. Ezzati, Curr. Chem. Lett. 2012, 1, 115.
| Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC38Xhsl2iur%2FL&md5=fe6577eb32d11926825df11da266496cCAS |

[27] J. Khalafy, M. Rimaz, M. Ezzati, R. H. Prager, Bull. Korean Chem. Soc. 2012, 33, 2890.
| Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC38XhsVyltb3M&md5=1ef0732b9a7e0b5ea7a440c2bc38c715CAS |

[28] J. Khalafy, M. Rimaz, L. Panahi, H. Rabiei, Bull. Korean Chem. Soc. 2011, 32, 2428.
| Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC3MXpslyrsbo%3D&md5=57637f1547c406df148eeac7302f6179CAS |

[29] M. Rimaz, J. Khalafy, N. Noroozi Pesyan, R. H. Prager, Aust. J. Chem. 2010, 63, 507.
| Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC3cXjvV2rtr0%3D&md5=8f70584fe972a5d0856a68d89f5f1babCAS |

[30] M. Rimaz, J. Khalafy, P. N. Moghadam, Aust. J. Chem. 2010, 63, 1396.
| Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC3cXhtFamurvL&md5=457c32c31570c4205bd167c19d67e088CAS |

[31] M. Rimaz, J. Khalafy, ARKIVOC 2010, ii, 110.

[33] H. A. Riley, A. R. Gray, Organic Syntheses 1943. Vol. II, p 509 (Wiley & Sons: New York, NY).

[34] A. I. Vogel, Practical Organic Chemistry 1974 (Longman Group Limited: London).