IJOC  Vol.7 No.3 , September 2017
Synthesis of Some Hexahydroquinazolinones Using K3AlF6(Al2O3/KF) as an Efficient Catalyst in Some Hexahydroquinazolinone Derivatives
ABSTRACT
A protocol for the synthesis of some 4-Aryl-1,3,4,6,7,8-hexahydroquinazolin-2,5(1H,6H)-diones (HHQs) was developed by means of a three-component condensation reaction of an aromatic aldehyde, 1,3-cylohexadione and urea in the presence of K3AlF6 (Al2O3/KF) as catalyst. This reaction is carried out under different conditions including 1) solvent free; 2) reflux in acetonitrile; 3) reflux in ethanol; 4) reflux in chloroform; and 5) reflux in water. In all conditions, the desired products are obtained in high yields after relatively short reaction times. Nevertheless, the reactions proceed faster and in higher yields when they were carried out in acetonitrile. This adopted protocol for some Biginelli-type products has offered the advantages of reusability of the catalyst, high yields and ease of separation of pure products. Furthermore, the catalyst is easily prepared, stabilized and efficiently used under reaction conditions.

1. Introduction

Six membered heterocyclic compounds, as important constituents exist in biologically active natural products [1] [2] . Among them, 3,4-dihydropyrimidi- nones (3,4-DHPMs) have exhibited important therapeutic and pharmacological properties [3] [4] [5] . Some of 3,4-DHPMs derivatives are also used as calcium channel blockers [6] . However, some of the cores of 3,4-DHPMs have an antiviral, antibacterial, antihypertensive and antitumor activities [7] [8] . Also, among them, 3,4-DHPMs derivatives, which are found as core units in many marine alkaloids, have been found to be potent HIV gp-120CD4 inhibitors [9] [10] [11] [12] . In 1893, Petero Biginelli, for the first time reported the synthesis of some 3,4-dihydropyrimidinones compounds (3,4-DHPMs) [12] . Octahydro- quinazolinone derivatives are a class of 3,4-DHPMs. These compounds, due to their molecular structure, have an important biological activity. However, these derivatives have been suggested to be a useful antibacterial activity and calcium antagonist activity [13] [14] [15] [16] [17] .

Fluoride ion is useful as a weak basic and non-nucleophilic catalyst in many organic chemical processes [18] [19] . Effectiveness of various inorganic solids as a support for potassium fluoride for promoting synthesis of organic compounds has been studied. Many supported fluoride systems, such as KF-SiO2, KF-mole- cular sieves have been found to be considerably and surprisingly more reactive than non-supported KF [20] [21] [22] [23] . Among them, the supported fluoride systems, potassium fluoride (KF) on activated alumina have been found to be surprisingly more reactive. Therefore, in 1979, Junko Yamawaki and a co- worker investigated a support of potassium fluoride on Alumina compound [24] . As well as, Weinstock et al. have examined the characterization of the actual catalytic agent in potassium fluoride on active alumina system. They have argued that K3AlF6 derives its basicity from the formation of KOH in the initial preparation of the solid supported material by the reaction of KF with the alumina support [25] .

Many derivatives fluorides complexes with the general A2BB’X6 composition are known to crystallize in the elpasolite (K2NaAlF6) (or ordered double perovskite) structure. The analysis of the data reported in literature shows that the information is available on K3AlF6(Al2O3/KF) being compared with its closest analogues cryolite Na3AlF6 and elpasolite K2NaAlF6. It has been reported that the room temperature of K3AlF6(Al2O3/KF) has a tetragonally distorted elpasolite-type structure, which transforms into the high symmetric cubic phase above 300˚C - 310˚C [26] [27] .

By having these facts in minds, we reported here for the first time, the synthesis, characterization, and experimental assays of a some series of some 4-Aryl-1, 3,4,6,7,8-hexahydroquinazolin-2,5(1H,6H)-diones (HHQs) derivatives using K3AlF6(Al2O3/KF) as catalyst.

2. Experimental

The FT-IR spectra were recorded on a FT-IR spectroscopy Perkinelemer BX-II. UV spectra (in EtOH) were recorded on a CINTRAL 101 spectrophotometer. 1H NMR and 13C NMR spectra were recorded on Bruker Avance 500 MHz spectrometer in DMSO-d6 with TMS as an internal standard. Mass spectra were obtained on Platform II spectrometer from Micromass; EI mode at 70 eV.

2.1. Preparation of K3AlF6(Al2O3/KF)

At first, the K3AlF6(Al2O3/KF) catalytic system was produced according to the literature [28] [29] . In this method, KF∙2H2O (20 g) was dissolved in water (80 ml), and then basic Al2O3 (30 g) was added. The resulting mixture was stirred at 65˚C - 75˚C for 1 h. The water was removed under reduced pressure, and the resulting powder was dried at 120˚C for 4 h to give active K3AlF6(Al2O3/KF).

2.2. General Procedure for the Synthesis of Hexahydroquinazolinone Derivatives Catalyzed by K3AlF6(Al2O3/KF)

A suspension of aromatic aldehydes (10 mmol), 1,3-cyclohexadione (10 mmol), urea (12 mmol) and K3AlF6 (Al2O3/KF) (0.05g) and acetonitrile (10 ml) were heated under reflux conditions for appropriate time. The progress of the reaction was monitored by TLC (eluent:n-hexane/ethyl acetate (5:1)). After completion of the reaction, the catalyst was separated by simple filtration. The crude product was produced by solvent evaporation under reduced pressure. The pro- duct was crystallized in ethanol.

4-phenyl-1,3,4,6,7,8-hexahydroquinazolin-2,5(1H,6H)-diones (2a):

M.P. = (227˚C - 229˚C, lit. [30] 226 - 228).

FT-IR (KBr): 3380.25, 2920.93, 1725.05, 1710.01, 1610.17 cm−1.

UV/Vis (EtOH): λmax(logε) = 265.66 nm (5.50).

4-(4-methylphenyl)-1,3,4,6,7,8-hexahydroquinazolin-2,5(1H,6H)-diones (2b):

FT-IR (KBr): 3336.85, 2941.02, 1722.08, 1602.37 cm−1.

1H NMR (500 MHz, DMSO-d6): δ = 1.90 (m, J = 7 Hz, 2H, H-8), 2.01 (m, J = 7.05 Hz, 2H, H-7), 2.19 (m, J = 6.9 Hz, 2H, H-9), 2.36 (m, J = 7.35 Hz, 3H, CH3), 2.94 (d, J = 10.7 Hz, 1H, H-4), 3.90 (d, J = 9.6 Hz, 1H, NH), 6.83 (s, 1H, NH), 6.94 (m, J = 7.55 Hz, 2H, Ar-H), 7.08 ppm (m, J = 7.85 Hz, 2H, Ar-H).

13C NMR (500 MHz, DMSO-d6): δ = 21.02, 29.05, 35.41, 37.24, 60.54, 101.41, 116.39, 128.72, 128.96, 134.02, 134.41, 141.68, 142.60, 195.83, 205.25 ppm.

MS (EI, 70 eV): m/z (%): 255.1 (M+, C15H15N2O2), 253.2 (M+-2H), 240.1 (M+-C15H14NO2), 227.2 (M+-C15H15O2), 164.1 (M+-C7H7), 148.1 (M+-C7H7-CH- NH-CO-NH), 131.1 (M+-C7H7-CH-CH=CH2), 119.1 (M+-C7H7-CH-NH), 71.1 (M+-NH-CH=CH-COH), 70.1 (M+-CH3-CO-CH=CH2), 57.1 (M+-NH-CO- NH), 51.1 (M+-CH2=CH-COH), 42.1 (M+-CH2-CH2-CH2).

UV/Vis (EtOH): λmax(logε) = 257.98 nm (5.49).

4-(3-methylphenyl)-1,3,4,6,7,8-hexahydroquinazolin-2,5(1H,6H)-diones (2c):

FT-IR (KBr): 3359.99, 2975.01, 1720.79, 1609.14 cm−1.

1HNMR (500 MHz, DMSO-d6): δ = 1.89 (m, J = 7.3 Hz, 2H, H-8), 2.10 (m, J = 7.4 Hz, 2H, H-7), 2.16 (m, J = 6.9 Hz, 2H, H-9), 2.38 (m, J = 6.7 Hz, 3H, CH3), 2.99 (d, J = 10.65 Hz, 1H, H-4), 3.90 (d, J = 9.6 Hz, 1H, NH), 6.78 (s, 1H, NH), 6.84 (m, J = 6.35 Hz, 1H, Ar-H), 6.91 (m, J = 7.4 Hz, 1H, Ar-H), 7.00 (m, J = 6.65 Hz, 1H, Ar-H), 7.04 (m, J = 7.45 Hz, 1H, Ar-H).

13C NMR (500 MHz, DMSO-d6): δ = 21.63, 29.09, 33.44, 37.14, 37.24, 100.44, 101.39, 127.58, 128.79, 129.43, 136.45, 144.74, 145.63, 196.27, 206.67 ppm.

MS (EI, 70 eV): m/z (%): 255.2 (M+; C15H15N2O2), 253.2 (M+-2H), 240.1 (M+- C15H14NO2), 227.2 (M+-C15H15O2), 164.1 (M+-C7H7), 148.1 (M+-C7H7-CH-NH- CO-NH), 131.1 (M+-C7H7-CH-CH=CH2), 119.1 (M+-C7H7-CH-NH), 71.1 (M+- NH-CH=CH-COH), 70.1 (M+-CH3-CO-CH=CH2), 57.1 (M+-NH-CO-NH), 51.1 (M+-CH2=CH-COH), 42.1 (M+-CH2-CH2-CH2).

UV/Vis (EtOH): λmax(logε) = 268.22 nm (5.50).

4-(2-methylphenyl)-1,3,4,6,7,8-hexahydroquinazolin-2,5(1H,6H)-diones (2d):

FT-IR (KBr): 3314.86, 2936.99, 1712.01, 1617.22 cm−1.

1H NMR (500 MHz, DMSO-d6): δ = 1.84 (m, J = 8.85 Hz, 2H, H-8), 2.08 (m, J = 8.3 Hz, 2H, H-7), 2.20 (m, J = 8.65 Hz, 2H, H-9), 2.36 (m, J = 5.65 Hz, 3H, CH3), 3.15 (d, J = 10.9 Hz, 1H, H-4), 4.01 (d, J = 10.65 Hz, 1H, NH), 6.90 (s, 1H, NH), 6.93 (m, J = 5 Hz, 1H, Ar-H), 6.97 (m, J = 5 Hz, 1H, Ar-H), 7.02 (m, J = 5 Hz, 2H, Ar-H).

13C NMR (500 MHz, DMSO-d6): δ = 21.35, 28.95, 35.98, 37.82, 61.81, 101.07, 101.89, 125.72, 126.18, 130.13, 135.49, 139.36, 144.54, 196.42, 206.32 ppm.

MS (EI, 70 eV): m/z (%): 255.1 (M+; C15H15N2O2), 253.2 (M+-2H), 240.1 (M+- C15H14NO2), 227.2 (M+-C15H15O2), 164.1 (M+-C7H7), 148.1 (M+-C7H7-CH-NH- CO-NH), 131.1 (M+-C7H7-CH-CH=CH2), 119.1 (M+-C7H7-CH-NH), 71.1 (M+- NH-CH=CH-COH), 70.1 (M+-CH3-CO-CH=CH2), 57.1 (M+-NH-CO-NH), 51.1 (M+-CH2=CH-COH), 42.1 (M+-CH2-CH2-CH2).

UV/Vis (EtOH): λmax(logε) = 258.40 nm (5.49).

4-(4-methoxyphenyl)-1,3,4,6,7,8-hexahydroquinazolin-2,5(1H,6H)-diones (2e):

FT-IR (KBr): 3389.23, 2959.93, 1722.04, 1601.58, 1375.17 cm−1.

1H NMR (500 MHz, DMSO-d6): δ = 1.86 (m, J = 5.7 Hz, 2H, H-8), 2.15 (m, J = 5.8 Hz, 2H, H-7), 2.39 (m, J = 5.75 Hz, 2H, H-9), 3.68 (m, J = 6.8 Hz, 3H, OCH3), 2.96 (d, J = 10.7 Hz, 1H, H-4), 3.88 (d, J = 10.75 Hz, 1H, NH), 6.84 (s, 1H, NH), 6.75 (m, J = 6.95 Hz, 2H, Ar-H), 7.10 (m, J = 6.45 Hz, 2H, Ar-H).

13C NMR (500 MHz, DMSO-d6): δ = 20.99, 29.07, 32.18, 55.38, 60.58, 100.50, 101.44, 113.71, 116.25, 116.47, 129.70, 137.51, 157.26, 195.87, 205.37 ppm.

MS (EI, 70 eV): m/z (%): 271.1 (M+, C15H15N2O3), 269.2 (M+-2H), 256.1 (M+- C15H14NO3), 255.1 (M+-CH3), 243.1 (M+-C15H15O3), 164.1 (M+-C7H7O-CH-NH- CO-NH), 147.1 (M+-C7H7O-CH-CH=CH2), 135.1 (M+-C7H7O-CH-NH), 107.1 (M+-C7H7O), 71.1 (M+-NH-CH=CH-COH), 70.1 (M+-CH3-CO-CH=CH2), 57.1 (M+-NH-CO-NH), 51.1 (M+-CH2=CH-COH), 42.1 (M+-CH2-CH2-CH2).

UV/Vis (EtOH): λmax(logε) = 265.66 nm (5.50).

4-(3-methoxyphenyl)-1,3,4,6,7,8-hexahydroquinazolin-2,5(1H,6H)-diones (2f):

FT-IR (KBr): 3374.80, 2941.18, 1719.71, 1614.34, 1374.19 cm−1.

1H NMR (500 MHz, DMSO-d6): δ = 1.89 (m, J = 5.45 Hz, 2H, H-8), 2.16 (m, J = 5.6 Hz, 2H, H-7) 2.39 (m, J = 5.65 Hz, 2H, H-9), 3.69 (s, 3H, OCH3), 2.98 (d, J = 10.7 Hz, 1H, H-4), 3.91 (d, J = 10.6 Hz, 1H, NH), 6.85 (s, 1H, NH), 6.62 (m, J = 6.8 Hz, 1H, Ar-H), 6.79 (d, J = 6.55 Hz, 1H, Ar-H), 7.07 (t, J = 6.85 Hz, 1H, Ar-H), 6.73 (s, 1H, Ar-H).

13CNMR (500 MHz, DMSO-d6): δ = 21.09, 29.12, 32.67, 55.22, 59.66, 100.48, 101.24, 120.72, 121.33, 128.64, 128.79, 146.48, 147.31, 196.31, 206.66 ppm.

MS (EI, 70 eV): m/z (%): 271.1 (M+, C15H15N2O3), 269.2 (M+-2H), 256.1 (M+- C15H14NO3), 255.1 (M+-CH3), 243.2 (M+-C15H15O3), 164.1 (M+-C7H7O-CH-NH- CO-NH), 147.1 (M+-C7H7O-CH-CH=CH2), 135.1 (M+-C7H7O-CH-NH), 107.1 (M+-C7H7O), 71.1 (M+-NH-CH=CH-COH), 70.1 (M+-CH3-CO-CH=CH2), 57.1 (M+-NH-CO-NH), 51.1 (M+-CH2=CH-COH), 42.1 (M+-CH2-CH2-CH2).

UV/Vis (EtOH): λmax(logε) = 275.12 nm (5.49).

4-(2-methoxyphenyl)-1,3,4,6,7,8-hexahydroquinazolin-2,5(1H,6H)-diones (2g):

FT-IR (KBr): 3260.57, 2955.07, 1710.75, 1611.88, 1383.05 cm−1.

1H NMR (500 MHz, DMSO-d6): δ = 1.87 (m, J = 4.65 Hz, 2H, H-8), 2.36 (m, J = 4.95 Hz, 2H, H-7), 2.38 (m, J = 5.35 Hz, 2H, H-9), 3.72 (s, 3H, OCH3), 2.90 (s, 1H, H-4), 4.55 (s, 1H, NH), 6.81 (s, 1H, NH), 7.05 (t, J = 7.8 Hz, 1H, Ar-H), 6.74 (t, J = 8.3 Hz, 1H, Ar-H), 6.88 (m, J = 7.55 Hz, 2H, Ar-H).

13C NMR (500 MHz, DMSO-d6): δ = 20.50, 20.98, 28.99, 37.26, 55.61, 101.60, 110.41, 111.47, 119.83, 126.55, 129.20, 131.69, 156.54, 196.07, 206.42 ppm.

MS (EI, 70 eV): m/z (%): 271.1 (M+; C15H15N2O3), 269.2 (M+-2H), 256.1 (M+- C15H14NO3), 256.1 (M+-CH3), 243.2 (M+-C15H15O3), 164.1 (M+-C7H7O-CH-NH- CO-NH), 147.1 (M+-C7H7O-CH-CH=CH2), 135.1 (M+-C7H7O-CH-NH), 107.1 (M+-C7H7O), 71.1 (M+-NH-CH=CH-COH), 70.1 (M+-CH3-CO-CH=CH2), 57.1 (M+-NH-CO-NH), 51.1 (M+-CH2=CH-COH), 42.1 (M+-CH2-CH2-CH2).

UV/Vis (EtOH): λmax(logε) = 267.79 nm (5.50).

4-(4-Chlorophenyl)-1,3,4,6,7,8-hexahydroquinazolin-2,5(1H,6H)-diones (2h):

FT-IR (KBr): 3321.06, 2938.79, 1716.15, 1614.90, 773.18 cm−1.

1H NMR (500 MHz, DMSO-d6): δ = 1.86 (m, J = 4.65 Hz, 2H, H-8), 2.04 (m, J = 6.65 Hz, 2H, H-7), 2.29 (m, J = 6.3 Hz, 2H, H-9), 3.06 (s, 1H, H-4), 4.64 (s, 1H, NH), 6.93 (s, 1H, NH), 7.12 (d, J = 7.85 Hz, 2H, Ar-H), 7.30 (d, J = 7.55 Hz, 2H, Ar-H).

13C NMR (500 MHz, DMSO-d6): δ = 20.53, 21.01, 28.93, 37.16, 101.55, 110.92, 126.23, 127.34, 128.93, 131.53, 132.50, 141.28, 196.22, 205.65 ppm.

MS (EI, 70 eV): m/z (%): 277.1 (M+, C14H13N2ClO2), 274.1 (M+-2H), 262.1 (M+-C14H12NClO2), 249.1 (M+-C14H13ClO2), 247.1 (M+-C14H11ClO2), 182.1 (M+- C6H4Cl-CH-NH-CO-NH), 151.1 (M+-C6H4Cl-CH-CH=CH2), 139.1 (M+-C6H4 Cl-CH-NH), 111 (M+-C6H4 Cl), 71.1 (M+-NH-CH=CH-COH), 70.1 (M+-CH3- CO-CH=CH2), 57.1 (M+-NH-CO-NH), 51.1 (M+-CH2=CH-COH), 42.1 (M+- CH2-CH2-CH2).

UV/Vis (EtOH): λmax(logε) = 262.24 nm (5.49).

4-(3-Chlorophenyl)-1,3,4,6,7,8-hexahydroquinazolin-2,5(1H,6H)-diones (2i):

FT-IR (KBr): 3074.81, 2984.07, 1718.42, 1603.53, 782.22 cm−1.

1H NMR (500 MHz, DMSO-d6): δ = 1.89 (m, J = 4.45 Hz, 2H, H-8), 2.18 (m, J = 4.8 Hz, 2H, H-7), 2.41 (m, J = 8.05 Hz, 2H, H-9), 3.04 (d, J = 10.85 Hz, 1H, H-4), 3.94 (d, J = 10.8 Hz, 1H, NH), 6.94 (s, 1H, NH), 7.21 (d, J = 7.45 Hz, 1H, Ar-H), 7.18 (m, J = 7.65 Hz, 1H, Ar-H), 7.16 (m, J = 7.45 Hz, 1H, Ar-H), 7.14 (m, J = 7.35 Hz, 1H, Ar-H).

13C NMR (500 MHz, DMSO-d6): δ = 20.87, 29.07, 32.95, 59.76, 100.48, 101.46, 125.71, 128.18, 129.50, 132.33, 132.40, 148.20, 195.95, 205.40 ppm.

MS (EI, 70 eV): m/z (%): 277.1 (M+, C14H13N2ClO2), 274.1 (M+-2H), 262.1 (M+-C14H12NClO2), 249.1 (M+-C14H13ClO2), 247.1 (M+-C14H11ClO2), 182.1 (M+- C6H4Cl-CH-NH-CO-NH), 151.1 (M+-C6H4Cl-CH-CH=CH2), 139.1 (M+-C6H4Cl- CH-NH), 111.1 (M+-C6H4 Cl), 71.1 (M+-NH-CH=CH-COH), 70.1 (M+-CH3- CO-CH=CH2), 57.1 (M+-NH-CO-NH), 51.1 (M+-CH2=CH-COH), 42.1 (M+- CH2-CH2-CH2).

UV/Vis (EtOH): λmax(logε) = 262.24 nm (5.49).

4-(2-Chlorophenyl)-1,3,4,6,7,8-hexahydroquinazolin-2,5(1H,6H)-diones (2j):

FT-IR (KBr): 3084.82, 2944.99, 1719.08, 1603.92, 796.06 cm−1.

1H NMR (500 MHz, DMSO-d6): δ = 1.89 (m, J = 5.95 Hz, 2H, H-8), 2.17 (m, J = 5.95 Hz, 2H, H-7), 2.39 (m, J = 6.95 Hz, 2H, H-9), 3.01 (d, J = 10.85 Hz, 1H, H-4), 3.88 (d, J = 9.65 Hz, 1H, NH), 6.87 (s, 1H, NH), 7.21 (m, J = 8.4 Hz, 1H, Ar-H), 7.19 (m, J = 8.05 Hz, 2H, Ar-H), 7.07 (d, J = 8.4 Hz, 1H, Ar-H).

13C NMR (500 MHz, DMSO-d6): δ = 20.87, 31.93, 32.55, 59.92, 100.45, 101.44, 127.71, 130.09, 130.15, 130.77, 143.91, 144.63, 196.37, 205.33 ppm.

MS (EI, 70 eV): m/z (%): 277.1 (M+; C14H13N2ClO2), 274.1 (M+-2H), 262.1 (M+-C14H12NClO2), 249.1 (M+-C14H13ClO2), 247.1(M+-C14H11ClO2), 182.1 (M+- C6H4Cl-CH-NH-CO-NH), 151.1 (M+-C6H4 Cl-CH-CH=CH2), 139.1 (M+-C6H4 Cl-CH-NH), 111.1 (M+-C6H4Cl), 71.1 (M+-NH-CH=CH-COH), 70.1 (M+-CH3- CO-CH=CH2), 57.1 (M+-NH-CO-NH), 51.1 (M+-CH2=CH-COH), 42.1 (M+- CH2-CH2-CH2).

UV/Vis (EtOH): λmax(logε) = 258.83 nm (5.49).

4-(4-Boromophenyl)-1,3,4,6,7,8-hexahydroquinazolin-2,5(1H,6H)-diones (2k):

FT-IR (KBr): 3174.20, 2945.97, 1720.89, 1603.05 cm−1.

1H NMR (500 MHz, DMSO-d6): δ = 1.89 (m, J = 8.95 Hz, 2H, H-8), 2.15 (m, J = 6.47 Hz, 2H, H-7), 2.40 (m, J = 4.19 Hz, 2H, H-9), 3.00 (d, J = 10.87 Hz, 1H, H-4), 3.88 (d, J = 10.85 Hz, 1H, NH), 6.91 (s, 1H, NH), 7.16 (d, J = 8.43 Hz, 2H, Ar-H), 7.30 (d, J = 8.43 Hz, 2H, Ar-H).

13C NMR (500 MHz, DMSO-d6): δ = 21.06, 28.95, 36.71, 56.71, 101.33, 101.44, 111.22, 127.74, 131.90, 132.24, 142.73, 150.16, 196.24, 205.46 ppm.

MS (EI, 70 eV): m/z (%): 321 (M+, C14H13N2BrO2), 318 (M+-2H), 306 (M+- C14H12NBrO2), 293 (M+-C14H13BrO2), 241 (M+-C14H13N2O2), 213.1 (M+-C6H4Br- CH-NH-CO-NH), 197 (M+-C6H4Br-CH-CH=CH2), 185 (M+-C6H4 Br-CH-NH), 157 (M+-C6H4Br), 71.1 (M+-NH-CH=CH-COH), 70.1 (M+-CH3-CO-CH=CH2), 57.8 (M+-NH-CO-NH), 51.1 (M+-CH2=CH-COH), 42.1 (M+-CH2-CH2-CH2).

UV/Vis (EtOH): λmax(logε) = 255.42 nm (5.48).

4-(3-Boromo phenyl)-1,3,4,6,7,8-hexahydroquinazolin-2,5(1H,6H)-diones (2l):

FT-IR (KBr): 3100.14, 2939.21, 1718.91, 1598.64 cm−1.

1H NMR (500 MHz, DMSO-d6): δ = 1.83 (m, J = 7.25 Hz, 2H, H-8), 2.13 (m, J = 6.35 Hz, 2H, H-7), 2.36 (m, J = 6.7 Hz, 2H, H-9), 3.03 (d, J = 10.85 Hz, 1H, H-4), 3.88 (d, J = 9.6 Hz, 1H, NH), 6.93 (s, 1H, NH), 7.31 (s, 1H, Ar-H), 7.22 (d, J = 7.6 Hz, 1H, Ar-H), 7.18 (d, J = 7.9 Hz, 1H, Ar-H), 7.11 (t, J = 7.7 Hz, 1H, Ar-H).

13C NMR (500 MHz, DMSO-d6): δ = 21.91, 36.71, 37.21, 57.71, 101.07, 110.27, 123.64, 126.75, 127.74, 130.28, 132.24, 145.78, 196.51, 206.52 ppm.

MS (EI, 70 eV): m/z (%): 321.1 (M+; C14H13N2BrO2), 318.1 (M+-2H), 306.1 (M+-C14H12NBrO2), 293.1 (M+-C14H13BrO2), 241.1 (M+-C14H13N2O2), 213.1 (M+- C6H4Br-CH-NH-CO-NH), 197.1 (M+-C6H4 Br-CH-CH=CH2), 185 (M+-C6H4Br- CH-NH), 157 (M+-C6H4Br), 71.1 (M+-NH-CH=CH-COH), 70.1 (M+-CH3-CO- CH=CH2), 57.8 (M+-NH-CO-NH), 51.1 (M+-CH2=CH-COH), 42.1 (M+-CH2- CH2-CH2).

UV/Vis (EtOH): λmax(logε) = 260.54 nm (5.49).

4-(2-Boromophenyl) -1,3,4,6,7,8-hexahydroquinazolin-2,5(1H,6H)-diones (2m):

FT-IR (KBr): 3328.76, 2935.95, 1713.36, 1615.06 cm−1.

1H NMR (500 MHz, DMSO-d6): δ = 1.86 (m, J = 6.1 Hz, 2H, H-8), 2.16 (m, J = 6.9 Hz, 2H, H-7), 2.37 (m, J = 5.4 Hz, 2H, H-9), 3.06 (s, 1H, H-4), 4.51 (s, 1H, NH), 7.03 (s, 1H, NH), 7.45 (d, J = 7.65 Hz, 1H, Ar-H), 7.12 (d, J = 3.85 Hz, 2H, Ar-H), 7.04 (d, J = 4.2 Hz, 2H, Ar-H).

13C NMR (500 MHz, DMSO-d6): δ = 21.06, 32.43, 37.21, 56.71, 101.63, 111.22, 123.64, 126.75, 127.74, 131.90, 132.24, 142.73, 196.24, 205.46 ppm.

MS (EI, 70 eV): m/z (%): 321.1 (M+; C14H13N2BrO2), 318.1 (M+-2H), 306.1 (M+-C14H12NBrO2), 293.1 (M+-C14H13BrO2), 241.1 (M+-C14H13N2O2), 213.2 (M+- C6H4Br-CH-NH-CO-NH), 197.1 (M+-C6H4Br-CH-CH=CH2), 185.1 (M+-C6H4 Br-CH-NH), 157.1 (M+-C6H4 Br), 71.1 (M+-NH-CH=CH-COH), 70.1 (M+-CH3- CO-CH=CH2), 57.8 (M+-NH-CO-NH), 51.1 (M+-CH2=CH-COH), 42.1 (M+- CH2-CH2-CH2).

UV/Vis (EtOH): λmax(logε) = 260.54 nm (5.49).

4-(4-Nitrophenyl)-1,3,4,6,7,8-hexahydroquinazolin-2,5(1H,6H)-diones (2n):

FT-IR (KBr): 3123.71, 2950.15, 1719.29, 1600.86, 1515.07, 1343.04 cm−1.

1H NMR (500 MHz, DMSO-d6): δ = 1.90 (m, J = 6.2 Hz, 2H, H-8), 2.19 (m, J = 6.95 Hz, 2H, H-7), 2.39 (m, J = 6.75 Hz, 2H, H-9), 3.08 (d, J = 10.95 Hz, 1H, H-4), 4.01 (d, J = 9.95 Hz, 1H, NH), 7.10 (s, 1H, NH), 7.49 (d, J = 8.55 Hz, 2H, Ar-H), 8.02 (d, J = 8.55 Hz, 2H, Ar-H).

13C NMR (500 MHz, DMSO-d6): δ = 21.03, 28.88, 32.33, 59.39, 100.45, 101.50, 123.00, 130.28, 145.60, 145.78, 153.76, 154.17, 196.51, 205.88 ppm.

MS (EI, 70 eV): m/z (%): 287.1 (M+; C14H13N3O4), 285.1 (M+-2H), 272.1 (M+- C14H12N2O4), 259.1 (M+-C14H13NO4), 258.1 (M+-C14H13N2O3), 241.1 (M+- C14H13N2O2), 193.1 (M+-C6H4 NO2-CH-NH-CO-NH), 165.1 (M+-C6H4NO2), 162.1 (M+-C6H4 NO2-CH-CH=CH2), 150.1 (M+-C6H4 NO2-CH-NH), 71.1 (M+- NH-CH=CH-COH), 70.1 (M+-CH3-CO-CH=CH2), 57.8 (M+-NH-CO-NH), 51.1 (M+-CH2=CH-COH), 42.1 (M+-CH2-CH2-CH2).

UV/Vis (EtOH): λmax(logε) = 262.67 nm (5.50).

4-(3-Nitrophenyl)-1,3,4,6,7,8-hexahydroquinazolin-2,5(1H,6H)-diones (2o):

FT-IR (KBr): 3119.91, 2953.97, 1719.17, 1601.62, 1524.68, 1351.53 cm−1.

1H NMR (500 MHz, DMSO-d6): δ = 1.96 (m, J = 4.65 Hz, 2H, H-8), 2.12 (m, J = 6.15 Hz, 2H, H-7), 2.38 (m, J = 6.65 Hz, 2H, H-9), 3.17 (d, J = 10.95 Hz, 1H, H-4), 4.01 (d, J = 10.05 Hz, 1H, NH), 7.04 (s, 1H, NH), 8.01 (s, 1H, Ar-H), 7.95 (d, J = 9.4 Hz, 1H, Ar-H), 7.48 (m, J = 8.05 Hz, 1H, Ar-H), 7.67 (m, J = 8.95 Hz, 1H, Ar-H).

13C NMR (500 MHz, DMSO-d6): δ = 20.78, 26.95, 31.87, 59.29, 114.93, 115.15, 120.95, 123.23, 129.23, 130.08, 147.65, 147.93, 196.04, 205.57 ppm.

MS (EI, 70 eV): m/z (%): 287.1 (M+, C14H13N3O4), 285.2 (M+-2H), 272.1 (M+- C14H12N2O4), 259.1 (M+-C14H13NO4), 258.1 (M+-C14H13N2O3), 241.1 (M+- C14H13N2O2), 193.1 (M+-C6H4NO2-CH-NH-CO-NH), 165.1 (M+-C6H4NO2), 162.1 (M+-C6H4 NO2-CH-CH=CH2), 150.1 (M+-C6H4NO2-CH-NH), 71.1 (M+- NH-CH=CH-COH), 70.1 (M+-CH3-CO-CH=CH2), 57.8 (M+-NH-CO-NH), 51.1 (M+-CH2=CH-COH), 42.1 (M+-CH2-CH2-CH2).

UV/Vis (EtOH): λmax(logε) = 263.52 nm (5.50).

4-(2,6-dichlorophenyl)-1,3,4,6,7,8-hexahydroquinazolin-2,5(1H,6H)-diones (2p):

FT-IR (KBr): 3321.96, 3164.29, 2948.40, 1715.82, 1636.05, 775.76, 753.90 cm−1.

1H NMR (500 MHz, DMSO-d6): δ = 1.90 (m, J = 5.95 Hz, 2H, H-8), 2.13 (m, J = 5.8 Hz, 2H, H-7), 2.38 (m, J = 5.25 Hz, 2H, H-9), 5.66 (s, 1H, H-4), 6.08 (s, 1H, NH), 7.59 (s, 1H, NH), 7.38 (m, J = 7.6 Hz, 2H, Ar-H), 7.24 (t, J = 7.95 Hz, 1H, Ar-H).

13C NMR (500 MHz, DMSO-d6): δ = 21.27, 26.43, 33.50, 51.41, 101.05, 104.85, 115.53, 127.56, 127.71, 129.58, 137.34, 150.97, 195.34, 205.34 ppm.

MS (EI, 70 eV): m/z (%): 310.1 (M+, C14H12N2Cl2O2), 309.1 (M+-2H), 295 (M+-C14H11NCl2O2), 282.1 (M+-C14H12Cl2O2), 275.1 (M+-Cl), 240.1 (M+-2Cl), 216.1 (M+-C6H3 Cl2-CH-NH-CO-NH), 185.1 (M+-C6H3 Cl2-CH-CH=CH2), 173 (M+-C6H3Cl2-CH-NH), 145 (M+-C6H3 Cl2), 70.2 (M+-CH3-CO-CH=CH2), 57.1 (M+-NH-CO-NH), 51.1 (M+-CH2=CH-COH), 42.1 (M+-CH2-CH2-CH2).

UV/Vis (EtOH): λ max(logε) = 271.63 nm (5.51).

3. Result and Discussion

Initially, we studied the Biginelli-type condensation reaction of benzaldehyde (1a), 1,3-cyclohexadione (CY), urea catalyzed by K3AlF6(Al2O3/KF) in different solvents under different conditions. (Scheme 1, Table 1). The effects of different factors were examined, including solvents, the reaction temperature, an amount of catalyst and the reaction time. The results have been summarized in Table 1.

Scheme 1. K3AlF6(Al2O3/KF) catalyzed synthesis of the 4-phenyl-1,3,4,6,7,8-hexahydro- quinazolin-2,5(1H,6H)-diones (2a).

Table 1. K3AlF6 catalyzed synthesis of 4-phenyl-1,3,4,6,7,8-hexahydroquinazolin-2,5(1H, 6H)-diones product (2a) under different conditions.

aIsolated yield; bTimes are given after maximum progression of the reaction.

Different solvents, such as H2O, EtOH, CHCl3 and CH3CN were used in this reaction. As well as, it was studied under solvent-free condition. The results show that the reaction was sluggish and the lower yield was observed under solvent free conditions.

According to the data presented in Table 1, the best conditions were achieved as a mixture of the following materials as aldehyde (10 mmol), 1,3-cyclohex- adione (10 mmol), urea (12 mmol) and K3AlF6(Al2O3/KF) (0.05 g) in acetonitrile (10 mL) as solvent under reflux condition (Scheme 2). The progress of reaction was followed by TLC using n-hexane/ethyl acetate (5:1) as eluents until the total disappearance of the 1,3-cyclohexadione was carried out. Then the product was washed with water, followed by crystallization from ethanol. The catalyst was separated by simple filtration and reused several times (Table 2). All the products are characterized by mp, Uv-vis, IR and 1H-NMR, 13C-NMR, Ms spectra. The results are reported in Table 3.

In summary, we have described an alternative and general method for the multicomponent synthesis of functionalized of some 4-Aryl-1,3,4,6,7,8-hexahy- droquinazolin-2,5(1H,6H)-diones using K3AlF6(Al2O3/KF) as a basic catalyst.

Scheme 2. K3AlF6(Al2O3/KF) catalyzed synthesis of some 4-aryl-1,3,4,6,7,8-hexahydro- quinazolin-2,5(1H,6H)-diones.

Table 2. Recyclability of K3AlF6 for synthesis of 4-phenyl-1,3,4,6,7,8-hexahydroquinazo- lin-2,5(1H,6H)-diones product (2a).

aIsolated yield; bTimes are given after maximum progression of the reaction.

Table 3. K3AlF6(Al2O3/KF) catalyzed synthesis of 4-aryl-3,4,6,7,8-hexahydroquinazolin- 2,5(1H,6H)-diones 2a-p.

The prospect of the reusability of this catalyst has also been demonstrated without compromising on the yield of the product. On the whole, the protocol presented here is an excellent alternative to many of the reported procedures by the use of K3AlF6(Al2O3/KF) as an environmentally benign and recyclable catalyst.

Consequently, the possibility to recycle catalyst was examined. As shown in Table 2, K3AlF6 could be reused without significant loss of activity.

Furthermore, we use the other 1,-3-dicarbonyl compounds for synthesis of the others 3,4-dihydropyrimidinoes. These data are reported in Scheme 3 and Table 4.

According to these data, we proposed the following mechanism (Scheme 4) for this method.

4. Conclusion

In summary, we have described an alternative and general method for the multicomponent synthesis functionalized of 4-Aryl-1,3,4,6,7,8-hexahydroquinazo-

Table 4. Synthesis of the others 3,4-dihydropyrimidiones using ethyl acetoacetate and dimedone as 1,3-carbonyl compound. (3 c, e, h, n) and (4 c, e, h, n).

Scheme 3. Synthesis the others 3,4-dihydropyrimidinones.

Scheme 4. Proposed the mechanism for this method.

lin-2,5-diones using Al2O3/KF as a basic catalyst. The prospect of the reusability of Al2O3/KF has also been demonstrated without compromising on the yield of the product. On the whole, the protocol presented here is an excellent alternative to many of the reported procedures by the use of Al2O3/KF as an environmentally benign and recyclable catalyst. Furthermore, these data show that the reactivity of K3AlF6 is more than KF and miture of Al2O3-KF. In this work, we observed the substituent effect in the synthesis of some hexahydroquinazolinones compounds.

Cite this paper
Mehrabi, M. , Farhadi, A. , Kiassat, A. (2017) Synthesis of Some Hexahydroquinazolinones Using K3AlF6(Al2O3/KF) as an Efficient Catalyst in Some Hexahydroquinazolinone Derivatives. International Journal of Organic Chemistry, 7, 240-253. doi: 10.4236/ijoc.2017.73018.
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