Synthesis, Resolution and Absolute Configuration of 2,3-Dihydro-2-Tert-Butyl-3-N-Benzylquinazolin-4-One: A Possible Chiral Auxiliary for Synthesis of β-Amino Cyclohexancarboxylic Acid

Fanny A. Cabrera-Rivera, Jaime Escalante

Centro de Investigaciones Químicas, Universidad Autónoma del Estado de Morelos, Cuernavaca, Mexico.

DOI: 10.4236/ijoc.2014.41007                

Abstract

3-Benzyl-2-(tert-butyl)-2,3-dihydroquinazolin-4(1H)-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.

Keywords

Chiral Auxiliary; 2-Tert-Butyl-Quinazolin-4-One

1. Introduction

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 A^1,3 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

Scheme 1. Synthesis of octahydroquinazolinone diastereoisomers.

Scheme 2. Synthesis of cisand trans-2-aminocyclohexanecarboxylic acid enantiomers.

Scheme 3. Synthesis of (±)-2,3.dihydro-4(1H)-quinazolinone rac-11.

Scheme 4. Synthesis of (S,S)- and (R,S)-diastereomers of quinazolinone (±)-11.

Scheme 5. Synthesis of enantiomerically pure quinazo linone (R)-11 and (S)-11.

Figure 1. Structure and solid-state confirmation for 13a.

Conflicts of Interest

The authors declare no conflicts of interest.

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