The One-Pot Synthesis of Pyrano[2,3-d]pyrimidinone Derivatives with 1,4-diazabicyclo[2.2.2]octane in Aqueous Media

Introduction

Owing to their pharmacological activity, Barbituric (BA) and Thiobarbituric (TBA) acids, as well as their various substituted derivatives, are very important compounds in biological chemistry and medicine. Their biological activity is mainly related to tautomerism and acid-base equilibria and, in turn, to the nature of substituents [1-3]. It is known that barbituric acid itself has no affect on the central nervous system [4], however it is a precursor to medical barbiturates which can be lethal in excessive amounts [5]. Other work has shown that in mice, barbituric acid will cause liver and kidney weight increase [6]. Barbituric acid is also a precursor to derivates that have been shown to have antibacterial activity [7,8] and for tumor inhibitory agents [9]. Therefore, determination of trace amounts of barbituric acid is very important both in studies of biological and industrial processes.

 

Scheme 1 Click here to View Scheme

aqueous media. Due to the diverse biological properties of this compound class, there is a widespread interest in their synthesis. Compounds with an uracil moiety antitumor, antibacterial, antihypertensive, vasodilator, bronchiodilator, hepatoprotective, cardiotonic, and antiallergic activities. Some of them exhibit antimalarial, antifungal analgesics, and herbicidal properties [10–17].

 

Previous methods for the synthesis of 7-amino-6-cyano-5-aryl-5H-pyrano[2,3-d]pyrimidin-(1H, 3H)-2,4-diones have been reported in which a two-component reaction between arylidene malononitrile with barbituric acid occurred under harsh thermal conditions [18]. Also, a microwave-assisted one-pot three-component cyclocondensation of barbituric acids, benzaldehyde derivatives, and alkylnitrile in the absence or presence of triethylamine Diammonium hydrogen phosphate (DAHP) [19-20] has been reported. These methods exhibit some disadvantages such as: harsh conditions, long reaction times, low yields, and effluent pollution.

 

Experimental

All of the chemical materials used in this work were purchased from Merck and Fluka and used without further purification. Melting points were determined with an Electro thermal 9100 apparatus and were uncorrected. IR spectra were obtained on an ABB FT-IR (FTLA 2000) spectrometer. 1HNMR and 13C NMR spectra were recorded on a Bruker DRX-500 AVANCE at 500 and 125MHz (respectively) using TMS as internal standard and DMSO-d6 as solvent. Mass spectra data were obtained using a GC-MS Hewlett Packard (EI, 20 e V) instrument.

 

Synthesis 7-Amino-6-cyano-5-(Aryl)4-oxo-2-thioxo-5H-pyrano[2,3-d] pyrimidinone

A solution of aromatic aldehyde 1 (1 mmol), malononitrile 2 (1.2 mmol ), barbituric acid 3 (1 mmol), and 1,4-diazabicyclo[2.2.2]octane (DABCO) (10 mol %) in H₂O (10 ml) and EtOH (10 ml) was stirred at room temperature for 2 h . After completion of the reaction, the solid product was collected by filtration and purified by washing with aqueous ethanol.

7-Amino-6-cyano-5-(4-bromophenyl)-4-oxo-2-thioxo-5H-pyrano[2,3-d]pyrimidinone (4a): White color powder, m.p. 236^◦C (dec.). IR (KBr) (νmax/cm⁻¹): 3370 (NH2), 3189 (NH), 2220 (C≡N), 1684 (C=O), 1567cm⁻¹. ¹H-NMR: δ=4.26 (s, 1H, H-5), 7.20 (d, 2H, ³ JHH= 8.2Hz, H-Ar), 7.48 (d, 2H, ³JHH=8.2Hz, H-Ar), 7.86 (brs, 2H, NH₂), 12.45 (brs, 1H, NH), 13.66 (brs, 1H, NH) ppm. ¹³C-NMR: δ=35.28 (CH), 58.48 (C-CN), 82.76 (C), 118.99 (C≡N), 120.00 (C-Br), 129.91 (2 CH), 132.19 (2 CH), 132.74 (C), 143.04 (C-NH₂), 157.42 (C=O), 160.34 (C), 173.97(C=S) ppm.

7-amino-6-cyano-5-(3-chlorophenyl)-4-oxo-2-thioxo-5H-pyrano [2,3-d]pyrimidinone (4b): White color powder, m.p. 237–238^◦C. IR (KBr) (νmax/cm⁻¹): 3373, 3196 (NH2), 3199, 3061 (NH), 2203 (C≡N), 1683 (C=O), 1569cm⁻¹. ¹H-NMR: δ=4.29 (s, 1H,H-5), 7.19 (brs, 2H,NH₂), 7.21–7.35 (m, 4 H, H-Ar), 12.45 (brs, 1H, NH), 13.50 (brs, 1H, NH).¹³C-NMR: δ=35.46 (CH), 57.95 (C-CN), 92.79 (C), 118.96 (C≡N), 126.46 (CH), 127.50 (CH), 128.3 (CH), 130.24 (CH), 132.95 (C-Cl), 146.10 (C), 151.96 (C-NH₂),157.57 (C=O), 160.31 (C), 173.98 (C=S) ppm. Mass: (C14H9ClN4O2S) m/z(%)= 334 (7, M²⁺), 332 (20, M⁺), 266 (100), 268 (43), 231(56), 221 (64).

7-Amino-6-cyano-5-(2,3-dichloro phenyl)-4-oxo-2-thioxo-5H-pyrano [2,3-d]pyrimidinone (4c): White color powder, m.p. 257–258^◦C. IR (KBr) (νmax/cm⁻¹): 3460, 3316 (NH₂), 3172,3064 (NH), 2190 (C≡N), 1671 (C=O), 1574cm⁻¹. ¹H-NMR:δ=4.85 (s, 1H, H-5), 7.28–7.35 (m, 4H, H-Ar and NH₂),7.51 (d, 1H, ³JHH=7.4Hz, H-Ar), 12.46 (brs, 1H, NH),13.70 (brs, 1H, NH) ppm. ¹³C-NMR: δ=34.03 (CH), 57.45(C-CN), 93.29 (C), 119.35 (C≡N), 129.20 (2 CH), 130.00(CH), 131.26 (C-Cl), 132.59 (C-Cl), 144.00 (C), 153.10 (CNH₂),158.57 (C=O), 160.93 (C), 174.87 (C=S) ppm.Mass:(C₁₄H₈Cl₂N₄O₂S)m/z(%)=370 (0.1, M⁴⁺), 368 (0.4,M²⁺), 366 (0.7, M⁺), 265 (100), 267 (41), 222 (18), 206(82), 187(23).

7-amino-6-cyano-5-(3-nitrophenyl)-4-oxo-2-thioxo-5Hpyrano[2,3-d] pyrimidinone (4d): White color powder, m.p. 233.5–234◦C.IR (KBr) (νmax/cm⁻¹): 3420, 3311 , 3197 (NH2), 2201(C≡N), 1687 (C=S), 1574 (C=O) cm⁻¹. ¹H-NMR: δ=4.52(s, 1H, H-5), 7.31 (brs, 2H, NH2), 7.60 (t, 1H,³JHH=7.0Hz, H-Ar), 7.76 (d, 1H, ³ JHH=7.0Hz, H-Ar),8.10 (d, 2H, ³JHH=1.2Hz, H-Ar), 12.46 (brs, 1H, NH),13.70 (brs, 1H, NH) ppm.¹³C-NMR: δ=35.48 (CH), 58.26(C-CN), 93.32 (C), 119.65 (C≡N), 122.92 (CH), 123.19(CH), 130.74 (CH), 135.52 (CH), 146.62 (C), 148.61 (CNO₂),152.85 (C-NH₂), 158.49 (C=O), 161.14 (C), 174.88(C=S) ppm. Mass: (C14H9N5O4S) m/z(%)=343 (2, M⁺),277 (100), 260 (23), 230 (17), 179 (49).

7-Amino-6-cyano-5-(4-nitrophenyl)-4-oxo-2-thioxo-5Hpyrano[2,3-d]pyrimidinone (4e):White color powder, m.p. 235–236^◦C. IR (KBr) (νmax/cm⁻¹): 3366(NH₂), 3190 (NH), 2197(C≡N), 1687 (C=O), 1569cm⁻¹. ¹H-NMR: δ=4.46 (s, 1H,H-5), 7.31 (brs, 2H, NH₂), 7.55 (d, 2H, ³ JHH=8.3Hz,H-Ar), 8.15 (d, 2H, ³ JHH=8.3Hz, H-Ar), 12.47 (brs, 1H,NH), 13.50 (brs, 1H, NH) ppm. 13C-NMR: δ=35.61 (CH),57.28 (C-CN), 92.43 (C), 118.80 (C≡N), 123.60 (2 CH),129.30 (2 CH), 146.49 (C), 151.16 (C-NO2), 152.09 (CNH2),157.57 (C=O), 160.31 (C), 174.09 (C=S) ppm.

7-Amino-6-cyano-5-(4-trifluoromethyl)-4-oxo-2-thioxo-5H-pyrano[2,3-d]pyrimidinone (4f): Pale yellow powder, m.p. 239–240^◦C. IR (KBr) (νmax/cm⁻¹): 3383 (NH₂), 3186 (NH), 2198 (C≡N), 1697 (C=O), 1671, 1637cm⁻¹. ¹H-NMR: δ=4.35(s, 1H,H-5), 7.26 (brs, 2H,NH₂), 7.48 (d, 2H, ³ JHH=8.1Hz, H-Ar), 7.66 (d, 2H, 3 JHH=8.1Hz, H-Ar), 12.46 (brs, 1H,

NH), 13.70 (brs, 1H, NH) ppm. ¹³C-NMR: δ=36.03 (CH), 58.57 (C-CN), 93.54 (C), 119.69 (C≡N), 126.08 (2 CH), 126.24 (2 CH), 129.34 (C), 130.98 (CF3), 149.02 (C), 152.82 (C-NH2), 158.34 (C=O), 161.09 (C), 174.88 (C=S) ppm. Mass: (C15H9F3N4O2S)m/z(%)=366 (28, M⁺), 300 (100), 231 (43), 221 (75), 202(57).

7-Amino-6-cyano-5-(2, 4-dichlorophenyl)-4-oxo-2-thioxo-5H-pyrano[2,3-d]pyrimidinone (4g): White color powder, m.p. 238.5–239.5^◦C. IR (KBr) (νmax/cm⁻¹): 3388 (NH₂), 3306, 3198(NH), 2196 (C≡N), 1687 (C=O), 1647cm⁻¹. ¹H-NMR:δ=4.75 (s, 1H, H-5), 7.25 (brs, 2H, NH₂), 7.33 (d, 2H, ³ JHH=7.9Hz, H-Ar), 7.38 (d, 1H, ³ JHH=7.9Hz H-Ar),12.54 (brs, 1H, NH), 13.64 (brs, 1H, NH) ppm. ¹³C-NMR:δ=38.69 (CH), 57.63 (C-CN), 88.01 (C), 119.43 (C≡N),128.47 (CH), 129.60 (CH), 132.81 (CH), 134.05 (C-Cl),140.91 (C-Cl), 150.37 (C-NH₂), 153.67 (C=O), 158.75 (C), 163.16 (C=S) ppm.

Results and discussion

Herein we report a simple synthesis of 7-amino-6-cyano-5-aryl-4-oxo-2-thioxo-5H-pyrano[2,3-d]pyrimidinones as a domino Knoevenagel–Michael condensation [21], catalyzed by 10% DAB-CO in aqueous media at room temperature (Scheme 1).Although we have not yet established the mechanism of the one-pot reaction between benzaldehyde derivatives,malononitrile and thiobarbitoric acid in the presence of DABCO, a possible explanation is presented in Scheme 2 We suggest that DABCO is an effective catalyst for the formation. The higher reactivity of the iminium group is utilized to facilitate Knoevenagel condensation between aryl aldehyde 1 and malononitrile 2, which proceeds via intermediate 5 and, after dehydration, olefin 7 is produced. DABCO also catalyzes the generation of a proposed carbonium thiobarbituric acid  and this intermediate  adds to olefin 6 to generate 4, after proton transfer, tautomerization andnhydrolysis of intermediate 8 (Scheme 2).

The structures of compounds 4(a-g) were deduced from their ¹H NMR, ¹³C NMR and IR spectral data and their molecular weight confirmed bymass spectrometry. ¹HNMR and ¹³C NMR spectroscopy were especially useful to elucidate the structures of products. Thus, all of the products exhibited a singlet peak at about δ =4.22–4.85ppm for H-5 in the ¹H NMR spectra, and also a distinctive signal at δ =35–36ppm for C-5 in the ¹³C NMR spectra. The mass spectra of

The proposed mechanism for the synthesis of 7-Amino-6-cyano-5-(Aryl)4-oxo-2-thioxo-5H-pyrano[2,3-d] pyrimidinone in aqueous media catalyzed by 1,4-diazabicyclo[2.2.2] octane (DABCO).

these compounds detected the expected molecular ion signals. Selected spectroscopic data have been given in general procedure section.

Table 1 shows the results obtained in the reaction of a series of representative aldehydes with malononitrile and thiobarbitoric acid. The effect of substituents on the aromatic ring did not show special effects in terms of yields under these reaction conditions.

 

Table 1: Synthesis with 10% mol Catalyst DABCO

 

Conclusion

We have developed an easier, practically convenient, novel, ecologically safe method for the synthesis of pyrano[2,3-d]pyrimidinone derivatives using a green chemistry protocol. The use of DABCO as a green catalyst not only gave high yields of products but also provided a procedure that does not use harmful organic solvents

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