3-Benzyl-2-(
tert-butyl)-2,3-dihydroquinazolin-4(1
H)-one
rac-11 was resolved via the preparation of diastereomers with
N-phthalyl-
L-alanine chloride and its absolute configuration was determined by X-ray crystallographic analysis. This heterocycle has potential as a substrate chiral in asymmetric induction due to the steric effects of its
tert-butyl group.
2,3-Dihydro-4(1H)-quinazolinones form an important class of bioactive compounds and these can easily be oxidized to their quinazolin-4(3H)-one analogues [1] . In general, the derivatives of the quinazolinones are considered as important building blocks [2] [3] for a large number of diverse alkaloids [4] [5] and present a wide range of biological and pharmaceutical activities [6] -[9] .
On the other hand, recently an efficient method for the conversion of anhydride isatoic into 4(3H)-quinazolinone 1 was described using (S)-a-methylbenzylamine as chiral auxiliary. Enantiomerically pure quinazolinone 1 was reduced diastereoselectively by hydrogenation with PtO2, resulting in octahydroquinazolinone diastereomers. Both cis-annelated derivatives (2 and 3) could be epimerized in the presence of t-BuO−K+, giving the corresponding trans-fused derivatives (4 and 5) respectively in good yields (Scheme 1) [10] -[12] .
Subsequently, the hydrolysis with HCl 6N of the four adducts (2-5) affords all four enantiomers of cisand trans-2-aminocyclohexanecarboxylic acid (6-9) in good yields (Scheme 2).
The present paper describes the synthesis and resolution of 2,3-dihydro-2-tert-butyl-3-N-benzylquinazolin- 4-one rac-11 as a possible precursor of cisand trans-2-aminocyclohexanecarboxylic acids. In this compound, it is important to mention that the tert-butyl group at C(2) adopts a pseudoaxial position, as shown by analysis of X-ray diffraction [10] -[12] , and we would expect higher induction in asymmetric hydrogenation reaction: the addition of the hydrogen on the syn face, leading to the exclusive formation of the only one diastereomer.
2. Results and Discussion
Synthesis of (±)-2,3-dihydroquinazolin-4(1H)-one rac-11.
Our research was focused in the preparation of starting material following the methodology previously reported by our group [11] -[13] in which a reaction between isatoic anhydride and benzylamine in ethyl acetate at 40˚C results in the corresponding aminobenzamide 10 with 90% yield. Next, cyclocondensation of 10 with pivalaldehyde in dichloromethane and p-toluenesulfonic acid monohydrate gives (±)-2,3,dihydro-4(1H)-quinazolinone rac-11 at 86% yield (Scheme 3).
It is noteworthy that was necessary to protect the reaction from light source since this would suffer photoinduced elimination and hence reduces the yield of compound 11 [11] .
The resolution was achieved by the preparation of the diastereomers 13a and 13b via condensation between the quinazolinone anion, formed with NaHMDS at −78˚C, and N-phthalyl-L-alanine chloride (S)-12 as the resoluting agent [14] . Separation of the diastereomers was accomplished by flash chromatography from hexane/ AcOEt (Scheme 4).
The assignment of the absolute configuration of the main products was achieved by X-ray diffraction analysis with the diastereomer 13a (Figure 1). In this way, we were able to determine the relative configuration S at C(2) in the quinazolinone system for diastereomer 13a, and consequently the opposite configuration for diastereomer 13b.
It is important to mention that X-ray crystal-structure determinations used to elucidate the stereochemical outcome of 13a revealed a pseudoaxial disposition of the tert-butyl group at C(2) (consequence of a powerful A1,3 effect) [15] -[21] , which could directs higher induction in addition toward the face opposite to this group in the hydrogenation reaction, leading to the exclusive formation of a single diastereomer.
Finally, as shown in Scheme 5, conversion of diastereoisomers 13a and 13b to the enantiomerically pure quinazolinones (R)-11 and (S)-11, was completed by hydrolysis with Bu4N+−OH in 75 and 67% yield respectively.
3. Conclusion
In conclusion, we present a new method for the preparation of enantiomerically pure quinazolinones (R)-11 and (S)-11. The interest for these quinazolinones as intermediaries is given by their potential use in the formation of
ReferencesZhang, Z., Lu, H., Yang, S. and Gao, J. (2010) Synthesis of 2,3-Dihydroquinazolin-4(1H)-Ones by Three-Component Coupling of Isatoic Anhydride, Amines, and Aldehydes Catalyzed by Magnetic Fe3O4 Nanoparticles in Water. Journal of Combinatorial Chemistry, 12, 643-646. http://dx.doi.org/10.1021/cc100047jWu, H., Xie, X. and Liu, G. (2010) Parallel Solution Phase Synthesis of 3,6,7-4(3H)-Quinazolinones and Evaluation of Their Antitumor Activities against Human Cancer. Journal of Combinatorial Chemistry, 12, 346-355.http://dx.doi.org/10.1021/cc900173sBowman, W., Elsegood, M., Stein, T. and Weaver, G. (2007) Radical Reactions with 3H-Quinazolin-4-Ones: Synthesis of Deoxyvasicinone, Mackinazolinone, Luotonin A, Rutaecarpine and Tryptanthrin. Organic & Biomolecular Chemistry, 5, 103-113. http://dx.doi.org/10.1039/b614075kKshirsagar, U., Puranik, V. and Argade, N. (2010) Total Synthesis of Proposed Auranthine. Journal of Organic Chemistry, 75, 2702-2705. http://dx.doi.org/10.1021/jo100400zMhaske, S. and Argade, N. (2006) The Chemistry of Recently Isolated Naturally Occurring Quinazolinone Alkaloids. Tetrahedron, 62, 9787-9826. http://dx.doi.org/10.1016/j.tet.2006.07.098Zeng F. and Alper, H. ,et al. (2010)One-Step Synthesis of Quinazo-lino[3,2-a]Quinazolinones via Palladium-Catalyzed Domino Addition/Carboxamidation Reactions Organic Letters 12, 3642-3644.Witt, A. and Bergman, J. (2000) Synthesis and Reactions of Some 2-Vinyl-3H-Quinazolin-4-Ones. Tetrahedron, 56, 7245-7253. http://dx.doi.org/10.1016/S0040-4020(00)00595-0Larksarp, C. and Alper, H. (2000) Palladium-Catalyzed Cyclocarbonylation of o-Iodoanilines with Heterocumulenes: Regioselective Preparation of 4(3H)-Quinazolinone Derivatives. Journal of Organic Chemistry, 65, 2773-2777.http://dx.doi.org/10.1021/jo991922rWang, M., Dou, G. and Shi, D. (2010) Efficient and Convenient Synthesis of Pyrrolo[1,2-a]Quinazoline Derivatives with the Aid of Tin(II) Chloride. Journal of Combinatorial Chemistry, 12, 582-586.http://dx.doi.org/10.1021/cc100062ePriego, J., Flores, P., Ortiz-Nava, C. and Escalante, J. (2004) Synthesis of Enantiopure Cis- and Trans-2-Aminocyclo- hexane-1-Carboxylic Acids from Octahydroquinazolin-4-Ones. Tetrahedron: Asymmetry, 15, 3545-3549.http://dx.doi.org/10.1016/j.tetasy.2004.08.032Cabrera-Rivera, F., Ortiz-Nava, C., Escalante, J., Hernandez-Perez, J. and Ho, M. (2012) Photoinduced Elimination in 2,3-Dihydro-2-Tert-Butyl-3-Benzyl-4(1H)-Quinazolinone: Theoretical Calculations and Radical Trapping Using TEMPO Derivatives. Synlett, 23, 1057-1063. http://dx.doi.org/10.1055/s-0031-1290492Escalante, J., Flores, P. and Priego, J. (2004) Synthesis of 2,3-Dihydro-4(1H)-Quinazolinones. Heterocycles, 63, 2019-2032. http://dx.doi.org/10.3987/COM-04-10130Escalante, J., Ortiz-Nava, C., Flores, P., Priego, J. and Garcia-Martinez, C. (2007) Synthesis, NMR and Crystallographic Studies of 2-Substituted Dihydroquinazolinones Derived from (S)-Phenylethylamine. Molecules, 12, 173-182.http://dx.doi.org/10.3390/12020173Escalante, J. and Gonzalez-Tototzin, M. (2003) Synthesis, Resolution and Absolute Configuration of Trans-4,5-Diphenyl-Pyrrolidin-2-One: A Possible Chiral Auxiliary. Tetrahedron: Asymmetry, 14, 981-985.http://dx.doi.org/10.1016/S0957-4166(03)00097-1Seebach, D., Lamatsch, B., Amstutz, R., Beck, A., Dobler, M., Egli, M., Fitzi, R., Gautschi, M., Herradon, B., et al. (1992) Structure and Reactivity of Five- and Six-Ring N,N-, N,O-, and O,O-Acetals: A Lesson in Allylic 1,3-Strain (A1,3 Strain). Helvetica Chimica Acta, 75, 913-934. http://dx.doi.org/10.1002/hlca.19920750326Murer, P., Rheiner, B., Juaristi, E. and Seebach, D. (1994) Enantioselective Synthesis of β-Amino Acids. 5. Stereoselective Reaction of Chiral Pyrimidinone Enolates with Aldehydes. Heterocycles, 39, 319-344.http://dx.doi.org/10.3987/COM-94-S(B)35Seebach D., Boog A. and Schweizer, W.B. ,et al. (1999)EPC-Synthesis of B-Amino Acid Derivatives through Lithiades Hydropyrimidines European Journal of Organic Chemistry 1999, 335-360.Ramirez-Quiros, Y., Balderas, M., Escalante, J., Quintana, D., Gallardo, It., Madrigal, D., Molins, E. and Juaristi, E. (1999) X-Ray Crystallographic Study of Substituted Perhydropyrimidinones. Extreme Changes in Ring Conformation. Journal of Organic Chemistry, 64, 8668-8680. http://dx.doi.org/10.1021/jo991297qJohnson, F. (1968) Allylic Strain in Six-Membered Rings. Chemical Reviews, 68, 375-413.http://dx.doi.org/10.1021/cr60254a001Hoffmann, R. (1989) Allylic 1,3-Strain as a Controlling Factor in Stereoselective Transformations. Chemical Reviews, 89, 1841-1860. http://dx.doi.org/10.1021/cr00098a009Broeker, J., Hoffmann, R. and Houk, K. N. (1991) Conformational Analysis of Chiral Alkenes and Oxonium Ions: Ab Initio Molecular Orbital Calculations and an Improved MM2 Force Field. Journal of the American Chemical Society, 113, 5006-5017. http://dx.doi.org/10.1021/ja00013a041Still, W., Kahn, M. and Mitra, A. (1978) Rapid Chromatographic Technique for Preparative Separations with Moderate Resolution. Journal of Organic Chemistry, 43, 2923-2925. http://dx.doi.org/10.1021/jo00408a041Sheldrick, G.M. (1998) SHELX97, Programs for Crystal Structure Analysis, Release 97-2. Institute for Inorganic Chemistry der Universität, Göttingen.Camps, P., Perez, F., Soldevilla, N. and Borrego, M. (1999) (R)- and (S)-3-Hydroxy-4,4-Dimethyl-1-Phenyl-2-Pyrrolidinone as Chiral Auxiliaries in the Enantioselective Preparation of α-Amino Acids. Tetrahedron: Asymmetry, 10, 493-509. http://dx.doi.org/10.1016/S0957-4166(99)00018-XCrystallographic Data Is Deposited at Cambridge Crystallographic Data Center (CCDC: No. 900252).