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Synlett 2008(16): 2495-2499  
DOI: 10.1055/s-2008-1078177
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

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

Mohamed Tabouazata,b, Ahmed El Louzia, Mohammed Ahmarb, Bernard Cazes*b
a LCPSOB, Université Mohammed V-Agdal, Avenue Ibn Battouta, BP 1014, Rabat, Morocco
b ICBMS-UMR 5246, Université LYON 1-CNRS, Bât. CPE-Lyon, 43 Bd. du 11 Novembre 1918, 69622 Villeurbanne, France
Fax: +33(4)72431214; e-Mail: cazes@univ-lyon1.fr;
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Publication History

Received 28 April 2008
Publication Date:
10 September 2008 (online)

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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.

Key words

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

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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.