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A facile microwave assisted one-pot synthesis of novel 1-methylhexahydroquinazolin-5(6H)-ones and bis-1-methylhexahydroquinazolin-5(6H)-ones.


Keeping in view the biological properties of octahydroquinazolines [1-3], we have recently reported [4, 5] the synthesis of hexahydroquinazolin-5(6H)-ones bearing phenyl and benzyl groups in position 1 of the ring and bis-hexahydroquinazolin-5(6H)-ones bearing phenyl group in position 1 of the ring. The biological properties of these molecules are under investigation. We now wish to report herein a short MW assisted synthesis of hexahydroquinazolin-5(6H)-ones and bis-hexahydroquinazolin-5(6H)-ones bearing methyl group in position 1 of quinazoline ring.

Material and Methods

Melting points were recorded by open capillary method and are uncorrected. The IR spectra were recorded on a Perkin-Elmer 983 spectrometer. [sup.1]H NMR (300 MHz) spectra were recorded on Bruker ACF-300 spectrometer. The chemical shifts ([delta] ppm) and the coupling constants (Hz) are reported in the standard pattern with reference to TMS as internal reference. FAB-mass spectra (MS) were measured on JEOL 3SX 102/DA-6000 Mass spectrometer using Argon as the FAB gas and m-nitrobenzylalcohol as the matrix. Elemental analyses were performed on a Vario-EL III instrument. Microwave irradiation was carried out in a domestic MW oven (Samsung CE2733G) operating at 2450 MHz. Enaminones 2a and 2b were synthesized by our reported procedure [6].

Synthesis of 1,3-substituted-1,2,3,4,7,8-hexahydroquinazolines (3a-e) and 1,3-substituted-7,7-dimethyl-1,2,3,4,7,8-hexahydroquinazolines (3f-j)

General procedure: A mixture of primary amine (1 mmol) and formaldehyde (2 mmol, 40% aqueous solution) in 1 mL of methanol was stirred for 5 minutes and to this was added a solution of enaminone 2 (1 mmol) in 4 mL methanol in one portion. The resulting reaction mixture was irradiated in a domestic microwave oven for 2-4 minutes at 180 watt. At the end of the reaction (tlc), methanol was distilled off under reduced pressure to give a gum which was purified by using chromatographic column (silica gel, EtOAc) to isolate 3a-j in 57-89 % yields.

1-Methyl-3-phenyl-1,2,3,4,7,8-hexahydroquinazolin-5(6H)-one (3a). Dark brown gum; yield 61%; IR (KBr): 1542 (vC=C), 1605 (vC=O) [cm.sup.-1]; [sup.1]H NMR (CD[Cl.sub.3]): [delta] 1.95-2.00 (m, 2H, [C.sub.7]-H), 2.33 (t, 2H, J = 6.3 Hz, [C.sub.8]-H), 2.45 (t, 2H, J = 6.3 Hz, [C.sub.6]-H), 2.96 (s, 3H, N-C[H.sub.3]), 4.18 (s, 2H, [C.sub.4]-H), 4.57 (s, 2H, [C.sub.2]-H), 6.87-6.98 (m, 3H, aromatic), 7.17-7.28 (m, 2H, aromatic); MS: m/z 243.2 (M[H.sup.+]). Anal. Calcd for [C.sub.15][H.sub.18][N.sub.2]O (242.32): C, 75.52; H, 8.20; N, 10.36. Found: C, 75.39; H, 8.16; N, 10.41%.

1-Methyl-3-benzyl-1,2,3,4,7,8-hexahydroquinazolin-5(6H)-one (3b). Dark brown gum; yield 84%; IR (KBr): 1559 (vC=C), 1636 (vC=O) [cm.sup.-1]; [sup.1]H NMR (CD[Cl.sub.3]): [delta] 1.90-2.01 (m, 2H, [C.sub.7]-H), 2.31 (t, 2H, J=6.0 Hz, [C.sub.8]-H), 2.45 (t, 2H, J=6.3 Hz, [C.sub.6]-H), 2.89 (s, 3H, N-C[H.sub.3]), 3.58 (s, 2H, [N.sub.3]-C[H.sub.2]), 3.66 (s, 2H, [C.sub.4]-H), 3.85 (s, 2H, [C.sub.2]-H), 7.26-7.39 (m, 5H, aromatic); MS: m/z 257.2 (M[H.sup.+]). Anal. Calcd for [C.sub.16][H.sub.20][N.sub.2]O (256.34): C, 74.97; H, 7.86; N, 10.93. Found: C, 74.91; H, 7.80; N, 10.99%.

1-Methyl-3-tolyl-1,2,3,4,7,8-hexahydroquinazolin-5(6H)-one (3c). Dark brown gum; yield 63%; IR (KBr): 1548 (vC=C), 1611 (vC=O) [cm.sup.-1]; [sup.1]H NMR (CD[Cl.sub.3]): [delta] 1.87-2.00 (m, 2H, [C.sub.7]-H), 2.28 (s, 3H, Ar-C[H.sub.3]), 2.33 (m, 2H, [C.sub.8]-H), 2.43 (m, 2H, [C.sub.6]-H), 2.94 (s, 3H, N-C[H.sub.3]), 4.15 (s, 2H, [C.sub.4]-H), 4.55 (s, 2H, [C.sub.2]-H), 6.87-6.91 (m, 4H, aromatic); MS: m/z 257.2 ([MH.sup.+]). Anal. Calcd for [C.sub.16][H.sub.20][N.sub.2]O (256.34): C, 74.97; H, 7.86; N, 10.93. Found: C, 74.89; H, 7.82; N, 10.88%.

1-Methyl-3-(4-chlorophenyl)-1,2,3,4,7,8-hexahydroquinazolin-5(6H)-one (3d). Pale yellow solid; yield 57%; mp 132[degrees]C; IR (KBr): 1542 (vC=C), 1611 (vC=O) [cm.sup.-1]; [sup.1]H NMR (CD[Cl.sub.3]): [delta] 1.96 (m, 2H, [C.sub.7]-H), 2.40 (t, 2H, J = 6.0 Hz, [C.sub.8]-H), 2.43 (t, 2H, J = 6.6 Hz, [C.sub.6] H), 2.99 (s, 3H, N-C[H.sub.3]), 4.14 (s, 2H, [C.sub.4]-H), 4.54 (s, 2H, [C.sub.2]-H), 6.89 (d, 2H, J=8.8 Hz, aromatic), 7.19 (d, 2H, J=8.8 Hz, aromatic); MS: m/z 277.2 (M[H.sup.+]). Anal. Calcd for [C.sub.15][H.sub.17]Cl[N.sub.2]O (276.76): C, 65.10; H, 6.19; N, 10.12. Found: C, 65.25; H, 6.14; N, 10.06%.

1,3-Dimethyl-1,2,3,4,7,8-hexahydroquinazolin-5(6H)-one (3e). Dark brown gum; yield 70%; IR (KBr): 1636 (vC=O) [cm.sup.-1]; [sup.1]H NMR (CD[Cl.sub.3]): [delta] 1.90-2.02 (m, 2H, [C.sub.7]-H), 2.32 (t, 2H, J = 6.0 Hz, [C.sub.8]-H), 2.44 (t, 2H, J = 6.6 Hz, [C.sub.6]-H), 2.90 (s, 3H, [N.sub.3]-C[H.sub.3]), 2.97 (s, 3H, [N.sub.1]-C[H.sub.3]), 3.42 (s, 2H, [C.sub.4]-H), 3.82 (s, 2H, [C.sub.2]-H); MS: m/z 181.1 (M[H.sup.+]). Anal. Calcd for [C.sub.10][H.sub.16][N.sub.2]O (180.25): C, 66.63; H, 8.95; N, 15.54. Found: C, 66.81; H, 8.89; N, 15.61%.

1,7,7-Trimethyl-3-phenyl-1,2,3,4,7,8-hexahydroquinazolin-5(6H)-one (3f). Pale yellow solid; yield 80%; mp 140[degrees]C; IR (KBr): 1540 (vC=C), 1599 (vC=O) [cm.sup.-1]; [sup.1]H NMR (CD[Cl.sub.3]): [delta] 1.01 (s, 6H, [C.sub.7]-C[H.sub.3]), 2.22 (s, 2H, [C.sub.8]-H), 2.25 (s, 2H, [C.sub.6]-H), 2.99 (s, 3H, [N.sub.1]-C[H.sub.3]), 4.18 (s, 2H, [C.sub.4]-H), 4.62 (s, 2H, [C.sub.2]-H), 6.90-6.97 (m, 3H, aromatic), 7.22-7.25 (m, 2H, aromatic) ; MS: m/z 271.2 (M[H.sup.+]). Anal. Calcd for [C.sub.17][H.sub.22][N.sub.2]O (270.37): C, 75.52; H, 8.20; N, 10.36. Found: C, 75.70; H, 8.15; N, 10.32%.

1,7,7-Trimethyl-3-benzyl-1,2,3,4,7,8-hexahydroquinazolin-5(6H)-one (3g). Pale yellow solid; yield 85%; mp 1420C; IR (KBr): 1566 (vC=C), 1609 (vC=O) [cm.sup.-1]; [sup.1]H NMR (CD[Cl.sub.3]): [delta] 1.10 (s, 6H, [C.sub.7]-C[H.sub.3]), 2.19 (s, 2H, [C.sub.8]-H), 2.32 (s, 2H, [C.sub.6]-H), 2.93 (s, 3H, [N.sub.1]-C[H.sub.3]), 3.67 (s, 2H, [C.sub.4]-H), 3.77 (s, 2H, [N.sub.3]-C[H.sub.2]), 3.99 (s, 2H, [C.sub.2]-H), 7.28-7.37 (m, 5H, aromatic); MS: m/z 284.8 (M[H.sup.+]). Anal. Calcd for [C.sub.18][H.sub.24][N.sub.2]O (284.40): C, 76.02; H, 8.51; N, 9.85. Found: C, 76.16; H, 8.47; N, 9.90%.

1,7,7-Trimethyl-3-tolyl-1,2,3,4,7,8-hexahydroquinazolin-5(6H)-one (3h). Pale yellow solid; yield 89%; mp 132[degrees]C; IR (KBr): 1540 (vC=C), 1594 (vC=O) [cm.sup.-1]; [sup.1]H NMR (CD[Cl.sub.3]): [delta] 1.02 (s, 6H, [C.sub.7]-C[H.sub.3]), 2.22-2.39 (m, 7H, [C.sub.8]-H + [C.sub.6]-H + Ar-C[H.sub.3]), 2.97 (s, 3H, [N.sub.1]-C[H.sub.3]), 4.16 (s, 2H, [C.sub.4]-H), 4.59 (s, 2H, [C.sub.2]-H), 6.87 (d, 2H, J = 8.1Hz, aromatic), 7.05 (d, 2H, J=8.1Hz, aromatic); MS: m/z 284.8 (M[H.sup.+]) Anal. Calcd for [C.sub.18][H.sub.24][N.sub.2]O (284.40): C, 76.02; H, 8.51; N, 9.85. Found: C, 75.92; H, 8.59; N, 9.80%.

1, 7,7-Trimethyl-3-(4-chlorophenyl)-1,2,3,4,7,8-hexahydroquinazolin-5(6H)-one (3i). Pale yellow solid; yield 75%; mp 174[degrees]C; IR (KBr): 1540 (vC=C), 1600 (vC=O) [cm.sup.-1]; [sup.1]H NMR (CD[Cl.sub.3]): [delta] 1.01 (s, 6H, [C.sub.7]-C[H.sub.3]), 2.12-2.24 (m, 4H, [C.sub.8]-H + [C.sub.6]-H), 2.99 (s, 3H, Nr C[H.sub.3]), 4.15 (s, 2H, [C.sub.4]-H), 4.60 (s, 2H, [C.sub.2]-H), 6.87 (d, 2H, J= 8.1Hz, aromatic), 7.19 (d, 2H, J= 8.1Hz, aromatic); MS: m/z 305.1 (M[H.sup.+]) Anal. Calcd for [C.sub.17][H.sub.21][N.sub.2]OCl (304.81): C, 66.99; H, 6.94 N, 9.19. Found: C, 66.80; H, 6.99; N, 9.23%.

1,3,7,7-Tetramethyl-1,2,3,4,7,8-hexahydroquinazolin-5(6H)-one (3j). Dark brown gum; yield 78%; IR (KBr): 1560 (vC=C), 1595 (vC=O) [cm.sup.-1]; [sup.1]H NMR (CDG3): [delta] 1.08 (s, 6H, [C.sub.7]-C[H.sub.3]), 2.18 (s, 2H, [C.sub.8]-H), 2.28 (s, 2H, [C.sub.6]-H), 2.41 (s, 3H, [N.sub.3]-C[H.sub.3]), 2.95 (s, 3H, [N.sub.1]-C[H.sub.3]), 3.45 (s, 2H, [C.sub.4]-H), 3.86 (s, 2H, [C.sub.2]-H); MS: m/z 209.2 (M[H.sup.+]). Anal. Calcd for [C.sub.12][H.sub.20][N.sub.2]O (208.30): C, 69.19; H, 9.68; N, 13.45. Found: C, 69.05; H, 9.65; N, 13.53%.

Synthesis of bis-Quinazolines 4a-d and 5a-d.

General Procedure: A mixture of diamine (0.5 mmol) and formaldehyde (2 mmol, 40% aqueous solution) in 1.5 mL methanol was shaken at room temperature for 5 minutes. To this mixture, a solution of enaminone 2 (1 mmol) in 5 mL methanol was added in one lot and the resulting mixture was irradiated in a domestic microwave oven for 2-4 minutes at 180 watt. At the end of the reaction (monitored by tlc), methanol was distilled off under reduced pressure to give a gum which was purified by using chromatographic column (silica gel, EtOAc) yielding 4 and 5 in 55-60% yields.

3,3-(Ethane-1,2-diyl)bis(1-methyl-1,2,3,4,7,8-hexahydroquinazoline-5(6H)-one) (4a). Dark brown gum; yield 55%; IR (KBr): 1543(vC=C), 1668 (vC=O) [cm.sup.-1]; [sup.1]H NMR (CD[Cl.sub.3]): [delta] 1.90-1.92 (m, 4H, [C.sub.7]-H + [C.sub.7]-H), 2.27 (t, 4H, J = 6.3 Hz, [C.sub.8]-H + [C.sub.8]-H), 2.42 (t, 4H, J = 6.0 Hz, [C.sub.6]-H + [C.sub.6]-H), 2.68 (s, 4H, -C[H.sub.2]-C[H.sub.2]-), 2.93 (s, 6H, [N.sub.1]-C[H.sub.3] + [N.sub.1]-C[H.sub.3]), 3.47 (s, 4H, [C.sub.4]-H + [C.sub.4]-H), 3.98 (s, 4H, [C.sub.2]-H + [C.sub.2]-H), MS: m/z 359.2 (M[H.sup.+]). Anal. Calcd for [C.sub.2][H.sub.30][N.sub.4][O.sub.2] (358.48): C, 67.01; H, 8.44; N, 15.63. Found: C, 67.21; H, 8.40; N, 15.69%.

3,3 -(Butane-1,4-diyl)bis(1-methyl-1,2,3,4,7,8-hexahydroquinazoline-5(6H)-one) (4b). Dark brown gum; yield 56%; IR (KBr): 1538 (vC=C), 1653 (vC=O) [cm.sup.-1]; [sup.1]H NMR (CD[Cl.sub.3]): [delta] 1.52-1.58 (m, 4H, [C.sub.7]-H + [C.sub.7]-H), 1.95 (t, 4H, J = 6.0 Hz, [C.sub.8]-H + [C.sub.8]-H), 2.222.27 (m, 4H, -C[H.sub.2]C[H.sub.2]C[H.sub.2]C[H.sub.2]-), 2.45 (t, 4H, J=6.0 Hz, [C.sub.6]-H + [C.sub.6]-H), 2.95 (s, 6H, [N.sub.1]-C[H.sub.3] + [N.sub.1]-C[H.sub.3]), 3.43 (s, 4H, -C[H.sub.2]C[H.sub.2]C[H.sub.2]C[H.sub.2]-), 3.88 (s, 4H, [C.sub.4]-H + [C.sub.4]-H), 4.98 (s, 4H, [C.sub.2]-H + [C.sub.2]-H); MS: m/z 387.1 (M[H.sup.+]). Anal. Calcd for [C.sub.22][H.sub.34][N.sub.4][O.sub.2] (386.53): C, 68.36; H, 8.87; N, 14.49. Found: C, 68.21; H, 8.22; N, 14.60%.

3,3-(Ethane-1,2-diyl)bis(1,7,7-trimethyl-1,2,3,4,7,8-hexahydroquinazoline-5(6H)-one) (4c). Dark brown gum; yield 60%; IR (KBr): 1557 (vC=C), 1669 (vC=O) [cm.sup.-1]; [sup.1]H NMR (CD[Cl.sub.3]): [delta] 1.06 (s, 12H, [C.sub.7]-C[H.sub.3] + [C.sub.7]- C[H.sub.3]), 2.17 (s, 4H, [C.sub.8]-H + [C.sub.8]-H), 2.27 (s, 4H, [C.sub.6]-H + [C.sub.6]-H), 2.68 (s, 4H, -C[H.sub.2]-C[H.sub.2]-), 2.99 (s, 6H, [N.sub.1]-C[H.sub.3] + [N.sub.1]-C[H.sub.3]), 3.55 (s, 4H, [C.sub.4]-H + [C.sub.4]-H), 4.03 (s, 4H, [C.sub.2]-H + [C.sub.2]-H); MS: m/z 415.3 (M[H.sup.+]). Anal. Calcd for [C.sub.24][H.sub.38][N.sub.4][O.sub.2] (414.58): C, 69.53; H, 9.24; N, 13.51. Found: C, 69.35; H, 9.28; N, 13.59%.

3,3 -(Butane-1,4-diyl)bis(1,7,7-trimethyl-1,2,3,4,7,8-hexahydroquinazoline-5(6H)-one) (4d). Dark brown gum; yield 58%; IR (KBr): 1557 (vC=C), 1650 (vC=O) [cm.sup.-1]; [sup.1]H NMR (CD[Cl.sub.3]): [delta] 1.06 (s, 12H, [C.sub.7]-C[H.sub.3] + [C.sub.7]-C[H.sub.3]), 1.55 (s, 4H, -C[H.sub.2]C[H.sub.2]C[H.sub.2]C[H.sub.2]-), 2.16 (s, 4H, [C.sub.8]-H + [C.sub.8]-H), 2.26 (s, 4H, [C.sub.6]-H + [C.sub.6]-H), 2.40 (s, 4H, -C[H.sub.2]C[H.sub.2]C[H.sub.2]C[H.sub.2]-), 2.89 (s, 6H, [N.sub.1]-C[H.sub.3] + [N.sub.1] -C[H.sub.3]), 3.47 (s, 4H, [C.sub.4]-H + [C.sub.4]-H), 3.91 (s, 4H, [C.sub.2]-H + [C.sub.2]-H); MS: m/z 443.3 (M[H.sup.+]). Anal. Calcd for [C.sub.26][H.sub.42][N.sub.4][O.sub.2] (442.64): C, 70.35; H, 9.56; N, 12.66. Found: C, 70.21; H, 9.51; N, 12.61%.

3,3 -(1,4-phenylene)bis(1-methyl-1,2,3,4,7,8-hexahydroquinazoline-5(6H)-one) (5a). Dark brown gum; yield 60%; IR (KBr): 1516 (vC=C), 1541 (vC=O) [cm.sup.-1]; [sup.1]H NMR (CD[Cl.sub.3]): [delta] 1.84-1.94 (m, 4H, [C.sub.7]-H + [C.sub.7]-H), 2.38 (t, 4H, J = 6.0 Hz, [C.sub.8]-H + [C.sub.8]-H), 2.52 (t, 4H, J = 1.8 Hz, [C.sub.6]-H + [C.sub.6]-H), 2.97 (s, 6H, [N.sub.1]-C[H.sub.3] + [N.sub.1]-C[H.sub.3]), 4.14 (s, 4H, [C.sub.4]-H + [C.sub.4] H), 4.54 (s, 4H, [C.sub.2]-H + [C.sub.2] -H), 6.90-6.96 (m, 4H, aromatic); MS: m/z 407.1 (M[H.sup.+]). Anal. Calcd for [C.sub.24][H.sub.30][N.sub.4][O.sub.2] (406.52): C, 70.91; H, 7.44; N, 13.78. Found: C, 70.75; H, 7.50; N, 13.69%.

3,3-(biphenyl-4,4-diyl)bis(1-methyl-1,2,3,4,7,8-hexahydroquinazoline-5(6H)-one) (5b). Dark brown gum; yield 55%; IR (KBr): 1533 (vC=C), 1609 (vC=O) [cm.sup.-1]; [sup.1]H NMR (CD[Cl.sub.3]): [delta] 1.86-1.90 (m, 4H, [C.sub.7]-H + [C.sub.7]-H), 2.21 (t, 4H, J = 6.3 Hz, [C.sub.8]-H + [C.sub.8]-H), 2.51 (t, 4H, J = 1.8 Hz, [C.sub.6]-H + [C.sub.6]-H), 2.94 (s, 6H, [N.sub.1]-C[H.sub.3] + [N.sub.1]-C[H.sub.3]), 4.05 (s, 4H, [C.sub.4]-H + [C.sub.4] H), 4.47 (s, 4H, [C.sub.2]-H + [C.sub.2] -H), 6.68-6.88 (m, 8H, aromatic); MS: m/z 483.7 (M[H.sup.+]). Anal. Calcd for [C.sub.30][H.sub.34][N.sub.4][O.sub.2] (482.62): C, 74.66; H, 7.10; N, 11.61. Found: C, 74.47; H, 7.15; N, 11.66%.

3,3-(1,4-phenylene)bis(1,7,7-trimethyl-1,2,3,4,7,8-hexahydroquinazoline-5(6H)-one) (5c). Dark brown gum in 56% yield; IR (KBr) 1548 (vC=C), 1647 (vC=O) [cm.sup.-1]; [sup.1]H NMR (CD[Cl.sub.3]): [delta] 1.01 (s, 12H, [C.sub.7]-C[H.sub.3] + [C.sub.7]-C[H.sub.3]), 2.17 (s, 4H, [C.sub.8]-H + [C.sub.8]-H), 2.25 (s, 4H, [C.sub.6]-H + [C.sub.6]-H), 2.95 (s, 6H, [N.sub.1]-C[H.sub.3] + [N.sub.1]-C[H.sub.3]), 4.10 (s, 4H, [C.sub.4]-H + [C.sub.4]-H), 4.53 (s, 4H, [C.sub.2]-H + [C.sub.2] -H), 6.87-6.91 (m, 4H, aromatic), MS: m/z 463.4 (M[H.sup.+]) Anal. Calc. for [C.sub.28][H.sub.38][N.sub.4][O.sub.2] (462.63): C, 72.69; H, 8.28; N, 12.11. Found: C, 72.51; H, 8.24; N, 12.17%

3,3 -(biphenyl-4,4 -diyl)bis(1,7,7-trimethyl-1,2,3,4,7,8-hexahydroquinazoline-5(6H)-one) (5d). Dark brown gum; 57% yield; IR (KBr): 1533 (vC=C), 1609 (vC=O) [cm.sup.-1]; [sup.1]H NMR (CD[Cl.sub.3]): [delta] 1.02 (s, 12H, [C.sub.7]-C[H.sub.3] + [C.sub.7] -C[H.sub.3]), 2.20 (s, 4H, [C.sub.8]-H + [C.sub.8] -H), 2.25 (s, 4H, [C.sub.6]-H + [C.sub.6]-H), 3.00 (s, 6H, [N.sub.1]-C[H.sub.3] + [N.sub.1]-C[H.sub.3]), 4.21 (s, 4H, [C.sub.4]-H + [C.sub.4]-H), 4.63 (s, 4H, [C.sub.2]-H + [C.sub.2] -H), 6.95-7.05 (m, 4H, aromatic), 7.43-7.48 (m, 4H, aromatic); MS: m/z 539.3 (M[H.sup.+]). Anal. Calcd for [C.sub.34][H.sub.42][N.sub.4][O.sub.2] (538.72): C, 75.80; H, 7.86; N, 10.40. Found: C, 75.64; H, 7.81; N, 10.47%.

Results and Discussion

Thus, when 3-methylaminocyclohexenone (2a) was treated with aniline and formaldehyde under the influence of microwaves, a product was obtained in 61% yields which was characterized as 1-methyl-3-phenyl-1,2,3,4,7,8-hexahydroquinazolin-5(6H)one (3a) on the basis of analytical and spectral data. The reaction of 2a with other primary amines and formaldehyde behaved in a similar manner and octahydroquinazolines 3b-e were isolated in 57-84% yields (scheme 1).


The infrared spectra of 3a-e showed strong peaks in the region of 1540 to 1636 [cm.sup.-1] due to extensively delocalized double bonds and carbonyl groups [6]. In the [sup.1]H NMR spectra of 3a-e, the methylene protons at C-2 resonated near 4.50 ppm except in 3b and 3e where they appeared in the vicinity of 3.80 ppm. This lowering in chemical shift could be attributed to the absence of delocalization of N-3 lone pair of electrons. Probably a similar explanation could be extended for the appearance of C[H.sub.2] protons at C-4 close to 4.15 ppm except in 3b and 3e where they were found to resonate near 3.50 ppm. While C[H.sub.2] protons at C-7 appeared as multiplets in the range of 1.90-2.00 ppm, those at C-6 and C-8 resonated close to 2.40 and 2.30 ppm, respectively. The methyl protons at N-1 gave singlets close to 2.90 ppm.

The Reactions of 2b with formaldehyde and primary amines were subsequently examined under similar conditions and the expected 1-methyl-3-alkyl/aralkyl/aryl-7,7-dimethyl-5-oxo-1,2,3,4,5,6,7,8-octahydroquinazolines 3f-j were isolated in 75-89% yields, whose structures could be established with the help of analytical and spectral data. The infrared spectra of 3f-j showed strong peaks in the region of 1540 to 1609 [cm.sup.-1]. The [sup.1]H NMR spectra of tetrahydropyrimidine rings of 3f-j were found to have a similar pattern as those of 3a-e. However, the six methyl protons at C-7 appeared as sharp singlets around 1.00 ppm and the C[H.sub.2] protons at C-6 and C-8 resonated in ranges of 2.25-2.99 and 2.18-2.24 ppm, respectively.

Encouraged by the successful synthesis of octahydroquinazolines 3a-j, we then turned our attention to the synthesis of bis-octahydroquinazolines. Thus, when enaminone 2a was reacted with 1,2-diaminoethane and formaldehyde under the influence of microwaves in methanol, a product 4a was isolated in 55% yield, the structure of which was established to be 3,3 -(ethane-1,2-diyl)bis(1-methyl-1,2,3,4,7,8-hexahydroquinazolin-5(6H)-one based on analytical and spectral data. The compound 2a gave the corresponding product 4b under identical conditions on reaction with 1,4diaminobutane and formaldehyde. We were thus able to connect two octahydroquinazoline rings through flexible aliphatic chains. Subsequently, with the intention to connect the two octahydroquinazoline rings through aromatic linkers, enaminones 2 were reacted with aromatic diamines and formaldehyde to give 5 in 5560% yields (scheme 1), the structures of which could be established with the help of spectral and analytical data.

The infrared spectra of 4a-d and 5a-d showed strong peaks in the range of 1516-1669 [cm.sup.-1] due to extensive delocalization of the enaminone moiety. The [sup.1]H NMR spectra of these dimers were found to have the same pattern as in the monomeric octahydroquinazolines except that the signals due to C[H.sub.2] protons of ethylene linkers appeared at 2.68 ppm while those in butylene appeared in the ranges of 2.45-2.46 and 1.55-2.17ppm. The dimeric structures of 4a-d and 5a-d were further supported by their mass spectra.


The present paper describes an efficient, clean, simple, fast and environment friendly strategy for the synthesis of hitherto unknown octahydroquinazolines and bis-octahydroquinazolines from easily accessible starting materials in good yields with promising biological properties. The methodology reported herein is an example of multicomponent reactions (MCRs).


The authors wish to thank the Principal, Rev. Fr. I. Warpakma, SDB for the facilities and Rev. Fr. Stephen Mavely, SDB and Rev. Fr. Joseph Nellanatt, SDB for their encouragement during the course of this investigation. MS thanks Fr. V. A. Cyriac, SDB for permission to carry out this work. The financial support from the UGC-New Delhi is gratefully acknowledged. Thanks are also due to SAIF-NEHU, Shillong for recording spectra.

References and Notes

[1] Sarac, S.; Yarim, M.; Ertan, M.; Kilic, F. S.; Erol, K. Arzneim-Forsc Drug Res. 2002, 52, 27.

[2] Yarim, M.; Sarac, S.; Kilic, F. S.; Erol, K. Farmaco 2003, 58, 17.

[3] Hamama, W.S.; Hammouda, M.; Afsahi, E. M. Z. Naturforsch 1988, 43B, 483.

[4] Chanda, K.; Dutta, M. C.; Vishwakarma, J. N. Indian J. Chem. 2006, 45B, 1076.

[5] Chanda, K.; Dutta, M. C.; Nongkhlaw, R. L.; Vishwakarma, J. N. E-J. Chem. 2009, 7, 281.

[6] Chanda, K.; Dutta, M. C.; Vishwakarma, J. N. Indian J. Chem. 2004, 43B, 2475.

Madhusudhan Saha (a), Enamul Karim (a), Philippe Helissey (b), Jai N. Vishwakarma (a) *, Rishanlang Nongkhlaw (c)

(This paper is dedicated to Rev. Fr. Dr. Stephen Mavely on his 60th Birth


(a) Organic Research Lab., Department of Chemistry, St. Anthony's College, Shillong-793 001, India

(b) Laboratoire de Chimie Therapeutique, UMR CNRS No. 8638, Universite Paris Descartes, Faculte des Sciences Pharmaceutiques et Biologiques, 4-Avenue de L'Observatoire, 75270 Paris Cedex 06 (France)

(c) Department of Chemistry, North-Eastern Hill University, Shillong-793 022, India

Received: 01 April 2010; revised: 21 July 2010; accepted: 02 September 2010.

* Corresponding author. E-mail:
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Title Annotation:Full Paper
Author:Saha, Madhusudhan; Karim, Enamul; Helissey, Philippe; Vishwakarma, Jai N.; Nongkhlaw, Rishanlang
Publication:Orbital: The Electronic Journal of Chemistry
Article Type:Report
Geographic Code:9INDI
Date:Jul 1, 2010
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