Biginelli-Atwal Reactions of (+)-Pulegone: An Entry into Chiral Hexahydroquinazolin-2-one Derivatives

Abstract

Biginelli-Atwal condensations of (+)-pulegone with (thio)ureas and guanidine afford hexahydroquinazoline-2(1H)-ones (-thiones) and/or 2-amino-1,3-thiazines with selectivities that depend on both the (thio)ureas and the experimental conditions. Carboannelation of these heterocyclic adducts with diethyl ethoxymethylenemalonate leads to uncommon pyrimidoquinazoline and pyrimidobenzothiazine systems.

pulegone - Biginelli-Atwal reactions - quinazolinone - carboannelation - pyrimidoquinazoline - pyrimidobenzothiazine

References and Notes

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Typical Experimental Procedure (Table 1, entry 4) - Synthesis of (7 R )-3,4,5,6,7,8-Hexahydro-4,4,7-trimethyl-quinazolin-2 (1 H )-one (14a) To a solution of urea 3a (1.2 g, 20 mmol) in EtOH (20 mL), was added 11 N HCl (0.9 mL, 10 mmol) and (+)-pulegone (13, 1.52 g, 10 mmol). The mixture was stirred at reflux for 14 h. Most of the EtOH was evaporated, so that a solid precipitated on cooling. The solid was filtered and washed with H₂O. Recrystallization from acetone gave 14a (2.33 g, 78%) as a white solid; mp 161-163 ˚C. TLC (SiO₂, EtOAc): R _f  = 0.18. IR (KBr, film): 3223, 2969, 2922, 1701, 1574, 1494, 1437, 1359, 1189, 1168, 740 cm^-¹. [α]_D ^²0 +61.1 (c 1.0; CH₂Cl₂). ^¹H NMR (300 MHz, CDCl₃): δ = 7.71 (s, 1 H,
N1-H), 5.76 (s, 1 H, N3-H), 1.95-2.00 (m, 3 H, H-5, H-7,
H-8), 1.60-1.75 (m, 3 H, H-5′, H-6, H-8′), 1.19 [s, 6 H, C(CH ₃)₂], 1.05-1.30 (m, 1 H, H-6′), 0.90 [d, ^³ J = 5.3 Hz, 3 H, CH(CH ₃)]. ^¹³C NMR (75.5 MHz, CDCl₃): δ = 155.9 (C=O), 126.8 (C-8a), 109.5 (C-4a), 55.3 (C-4), 34.3 (C-8), 31.4 (C-5), 29.2 and 29.0 [C(CH₃)₂], 28.7 (C-7), 22.5 (C-6), 21.7 [CH(CH₃)]. Anal. Calcd for C₁₁H₁₈N₂O: C, 66.97; H, 9.34; O, 23.69. Found: C, 66.88; H, 9.47; O, 23.65.

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(7R)-3,4,4a,5,6,7-Hexahydro-1,4,4,7-tetramethylquin-azolin-2 (1H)-one(18) was obtained as a single diastereomer to which the cis-18 structure was tentatively assigned. Indeed, the ^¹H NMR and ^¹³C NMR spectra [δ (^¹H): singlets at 0.97 and 1.13 ppm; δ (^¹³C): 23.2 and 27.2 ppm] of this diastereomer show two very differentiated gem-methyl groups, which is in consideration of a CH₃/H (on C-7 and
C-4a carbon atoms) cis-relationship after comparison of the molecular models of both cis- 18 and trans-18 structures. This cis-relationship is also predicted according to the plausible mechanistic pathways for the formation of hexahydroquinazolinones 14b and 18: i) acid-catalyzed 1,4-addition of the less-hindered nitrogen atom of methylurea 3b to the conjugated enone system giving a cis-diequatorial cyclohexanone intermediate; ii) intramolecular condensation of the NHMe nitrogen on the carbonyl group; iii) β-elimination of a proton, H-4a or H-8 proton, giving rise to hexahydroquinazolinone 14b or cis-18, respectively.

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