3-(N,N-diacylamino)quinazolin-4(3H)-ones as enantioselective acylating agents for amines

Article abstract of DOI:10.1016/S0040-4039(00)00138-6

The presence of an N-N chiral axis in a 3-(N-benzoyl-N- isobutanoyl)aminoquinazolin-4(3H)-one (DAQ) bearing a chiral substituent in the 2-position of the quinazolinone allows separation of two enantiopure diastereoisomers; one of these diastereoisomers reacts with racemic 2- methylpiperidine to give (R)(+)-1-benzoyl-2-methylpiperidine (95% ee) and (S)-2-methylpiperidine (91% ee) even using stoichiometric quantities of reagents (1 equiv. DAQ: 2 equiv. amine). (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00138-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 2239–2242
3-(N,N-Diacylamino)quinazolin-4(3H)-ones as enantioselective
acylating agents for amines
Abdullah G. Al-Sehemi, Robert S. Atkinson,∗ John Fawcett and David R. Russell
Department of Chemistry, University of Leicester, Leicester LE1 7RH, UK
Received 9 December 1999; accepted 18 January 2000
Abstract
The presence of an N–N chiral axis in a 3-(N-benzoyl-N-isobutanoyl)aminoquinazolin-4(3H)-one (DAQ) bearing
a chiral substituent in the 2-position of the quinazolinone allows separation of two enantiopure diastereoisomers;
one of these diastereoisomers reacts with racemic 2-methylpiperidine to give (R)(+)-1-benzoyl-2-methylpiperidine
(95% ee) and (S)-2-methylpiperidine (91% ee) even using stoichiometric quantities of reagents (1 equiv. DAQ: 2
equiv. amine). © 2000 Elsevier Science Ltd. All rights reserved.
We have shown previously that 3-diacylaminoquinazolin-4(3H)-ones (DAQs) containing a chiral
centre in one of the acyl groups e.g. 1 are separable into diastereoisomers.1 The additional chiral element
in DAQ 1 is the N–N bond (a chiral axis) since two non-interconverting rotamers around this bond are
present at room temperature: interconversion between the two diastereoisomers of DAQ 1 by rotation
around the N–N bond takes place only on heating (∆G#=121 kJ mol−1). We have also shown that 3-
N,N-diacetylaminoquinazolinones e.g. 2 are highly selective acetylating agents for primary amines in the
presence of secondary amines and for the less sterically hindered of two secondary amines.2 For example,
DAQ 2 reacts exclusively with piperidine in the presence of 2-methylpiperidine and with dimethylamine
in the presence of diethylamine. This chemoselectivity in the reaction of DAQ 2 with the less hindered
of two secondary amines we now find has a stereoselective counterpart — the preferential reaction of a
diastereo- and enantio-pure DAQ with one enantiomer of a racemic secondary amine thus bringing about
kinetic resolution of the amine.3
We prepared DAQ diastereoisomers 4a and 4b by sequential N-benzoylation and N-isobutanoylation
of 3-aminoquinazolinone 3 which was itself prepared from (L)-valine in five steps without the need for
chromatography (Scheme 1).4 Separation of the DAQ diastereoisomers 4a and 4b, formed in a 1.6:1
ratio, was accomplished by Kieselgel chromatography5 and an X-ray structure determination was carried
out on the crystalline slower-eluted diastereoisomer 4b (Fig. 1).6
In this crystal structure, the quinazolinone and imide planes,7 linked by the N–N bond, are, as expected,
approximately orthogonal but the conformations of the imide carbonyl groups are both exo and not
∗
Corresponding author.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00138-6
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Scheme 1. Reagents: (i) NaNO2, HOAc; (ii) SOCl2; (iii) methyl anthranilate; (iv) NH2NH2, EtOH; (v) TBDMSCl, imidazole,
DMF; (vi) PhCOCl, pyr.; (vii) PriCOCl, pyr
Fig. 1. Molecular structure of 4b. Displacement parameters are shown at the 30% probability level, H atoms are omitted for
clarity
exo–endo as has previously been found for other DAQs e.g. 1.1 As can be seen from Fig. 1, the benzoyl
group has its benzene ring out of the plane of the carbonyl (dihedral angle 50.1° between the two planes).
Moreover, the carbonyl group of the benzoyl is twisted out of the plane which would allow overlap of its
π-bond with the p-orbital on the imide nitrogen.8 The isobutanoyl group, by contrast, is oriented such
that it can enjoy normal amide resonance with this imide nitrogen.
Both the non-amidic nature of the benzoyl carbonyl group and the absence of conjugation in
the benzoyl unit presumably account for the completely chemoselective attack by amines, e.g. 2-
methylpiperidine, on the benzoyl group of DAQ 4b, i.e. the structures in the crystal and in solution

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are probably similar. Likewise, DAQ 4a (an oil) also undergoes attack by 2-methylpiperidine exclusively
at the benzoyl group.9
Both DAQs 4a and 4b react enantioselectively with amines. Thus, reaction of DAQ 4a (1 equiv.)
with 2-methylpiperidine (2 equiv.) was carried out in dichloromethane at 5°C for 12 h. Unreacted 2-
methylpiperidine was extracted with aqueous hydrochloric acid (2M) and the free amine converted
to the N-benzoylamide 50 (Scheme 2). The benzoylamide 5 formed in the reaction of 4a with 2-
methylpiperidine was isolated by flash chromatography of the crude reaction product obtained from the
dichloromethane layer; the only other product isolated was the 3-isobutanoylaminoquinazolinone 6. A
summary of the yields, and calculated ees of products isolated from these reactions is given in Scheme
2.10
Scheme 2.
The ees in Scheme 2 were based on the optical rotation of a sample of (S)-1-benzoyl-2-
methylpiperidine [α]D+32.9 (c=0.8, CHCl3) prepared from (S)-2-methylpiperidine {[α]D 8.9
(c=2, EtOH) lit.11 7.2 (c=6, EtOH)} itself obtained from the racemic amine by resolution using
(R)-mandelic acid.11 The enantiopurity of this (S)-2-methylpiperidine was independently confirmed by
its derivatisation with (S)-2-acetoxypropanoyl chloride and by comparison of the NMR spectrum of the
product with that of the mixture of diastereoisomers formed from racemic 2-methylpiperidine with the
same acid chloride: at 400 MHz and 50°C the OCOCH3 signals in the NMR spectrum of this mixture
were completely separated.
A quantitative measure of the enantioselectivity of DAQ 4a with 2-methylpiperidine was obtained
by separation of enantiomers of this amine by classical resolution and by measuring the kinetics of the
reactions of each of these enantiomers with DAQ 4a. The relative rates of faster reacting:slower reacting
amine enantiomers [k(R):k(S)] was calculated to be 27:1.
Reaction of DAQ 4b (1 equiv.) with 2-methylpiperidine (2 equiv.) is slower and requires 3 days for
complete reaction: significantly, it is the other enantiomer of 2-methylpiperidine which reacts giving N-
benzoylamide 50 (80% ee). Thus in these benzoylations with DAQs 4a and 4b it is the chiral axis which
controls the sense of enantioselectivity.
Acknowledgements
We thank the Ministry of Education, Saudi Arabia, for funding (to A.G.Al-S).
References
1. Atkinson, R. S.; Barker, E.; Edwards, P. J.; Thomson, G. A. J. Chem. Soc., Perkin Trans. 1 1996, 1047.
2. Atkinson, R. S.; Barker, E.; Sutcliffe, M. J. Chem. Commun. 1996, 1051.

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3. We have previously shown that partial kinetic resolution of α-phenylethylamine with a DAQ was possible (Ref. 1).
4. cf. Atkinson, R. S.; Ayscough, A. P.; Gattrell, W. T.; Raynham, T. M. J. Chem. Soc., Perkin Trans. 1 1998, 2783.
5. Hunt, B. J.; Rigby, W. Chem. and Ind. 1967, 1868.
6. Crystal data: 4a, C29H39N3O4Si, M=521.72, orthorhombic, space group P212121, a=9.061(1), b=15.181(2), c=21.423(12)
Å, V=2947(2) Å3, Z=4, Dc=1.176 g cm−3, F(000)=1120, µ=0.116 mm−1, crystal 0.72×0.37×0.22 mm, radiation Mo-Kα
(λ=0.71069 Å), 160(2) K, 3253 data, 334 parameters, R1[F2>2σ(F2)]=0.0537, wR2=0.1354 (all data).
7. The imide nitrogen of DAQ 4a is not exactly planar (Σ bond angle=353.3°).
8. For references to other twisted amides, see: Kondo, K.; Fujita, H.; Suzuki, T.; Murakami, Y. Tetrahedron Lett. 1999, 40,
5577 and references cited therein.
9. By comparison, a competitive reaction of benzoyl chloride and isobutanoyl chloride for 2-methylpiperidine gave a 3:2 ratio
of the corresponding amides, respectively.
10. The enantiopurity of the unreacted enantiomer was also determined by its reaction with (S)-α-acetoxylpropanoyl chloride:
the de of the resulting amide was 89% as measured by NMR.
11. Craig, J.; Pindlar, A. R. J. Org. Chem. 1971, 32, 3649.