The title compounds (DAQs) are chiral when the two N-acyl groups are different because of the absence of rotation around the N-N bond (a chiral axis). Enantiopure DAQs have been obtained by incorporation of a chiral centre in enantiopure form either into the substituent at the Q2-position or into one of the N-acyl groups, or into both, followed by separation of diastereoisomers. This separation is unnecessary in one case because conversion of the N-monoacylaminoquinazolinone (MAQ) into the DAQ is completely diastereoselective. Neither is separation of diastereoisomers necessary with 3-[N,N-di-(S)-2-acetoxypropanoylamino]-2-diphenylmethylquinazolin-4(3H)-one 37a: this DAQ 37a has its N-N bond rendered a chiral axis by the bias in its imide moiety wholly in favour of one exo/endo conformation.The high chemoselectivity exhibited by N, N-diacetyl- or N, N-dibenzoylaminoquinazolinones in reaction with the less hindered of two secondary amines (pyrrolidine in the presence of 1 eq. of piperidine) has a stereoselective counterpart: reaction of the above enantiopure DAQs enantioselectively with racemic amines leading to kinetic resolution. Using 1 eq. of DAQ and 2 eq. of amine, both the derivatised and unreacted amine enantiomers are recovered with high enantiomeric excess (ee) (better than 90% ee in some cases). Some of the higher ees are found in the recovered amides where non-chemoselective attack on both N-acyl groups of the DAQ has occurred: from the opposite configurations of the amine component in the two amides and from the low enantiopurity of the recovered unreacted amine, reaction of each of the N-acyl groups with complementary enantiomers of the amine is occurring (parallel kinetic resolution).Although higher ees are, in general, obtained using secondary amines, high ees are obtained in some cases using 1-phenylethylamine and, in particular, amino acid esters (valine and alanine).The sense of enantioselectivity in the reactions of these DAQs with amines is controlled by the configuration of the N-N axis: replacing the Q group in an N-(S)-2-acetoxypropanoyl-N-acetyl-bearing DAQ by phthalimide, thus eliminating the N- N chiral axis, drastically reduces the level of kinetic resolution.

(R)-3-Amino-2-[1-(2-hydroxyethoxy)ethyl]quinazolin-4(3H)-one 10 was prepared in 62% yield without the need for chromatography and O-cinnamoylated; reaction with lead tetra-acetate gave aziridine 12 as a single diastereoisomer in quantitative yield which was converted into the β-amino acid ester 15 corresponding to overall enantioselective addition of ammonia to the double bond of cinnamic acid.

Reaction of 2-substituted-3-acetoxyaminoquinazolin-4(3H)-ones (QNHOAc) with cyclohexa-1,3-diene or cyclohexa-1,4-diene (2 equiv.) gives, besides the expected aziridination products, stable dihydroaromatic by-products formally arising by insertion of [QN:] into one of the doubly allylic C-H bonds. An analogous insertion into the methylene C-H bonds of 9,10-dihydroanthracene or xanthene (1.5-2 equiv.) occurs. Using 3-acetoxyamino-2-[(S)-2,2-dimethyl-1-hydroxypropyl]quinazolin-4(3H)-one 2 (Q(1)NHOAc) in the presence of titanium(IV) t-butoxide, insertion into cyclohexa-1,3-diene takes place completely diastereoselectively and the configuration at the cyclohexadienyl ring carbon has been correlated with that at the 6-position of the major aziridine diastereoisomer co-produced in the reaction. A mechanism involving concerted insertion into the C-H bond of the diene by QNHOAc is proposed with endo-overlap of both double bonds of the diene with the Q group in the transition state. (C) 2002 Elsevier Science Ltd. All rights reserved.

Reaction of (S)-3-acetoxyamino-2-[1-(t-butyldimethylsilyloxy)ethyl]quinazolin-4(3H)-one 5 (Q(1)NHOAc) with styrene and R(beta)-substituted E-styrenes (R = SiMe3, Me, CH2 Cl, CHCl2) gives the corresponding aziridines diastereoselectively. The diastereoselectivity increases in the same sense from 5 : 1 --> 20 : 1 as the electron-withdrawing character of R increases [H( Me), CH2 Cl, CHCl2] but is accompanied by a decrease in yield of aziridine. A similar increase in diastereoselectivity is found in the reaction of 3-acetoxyamino-2-(2,3,3-trimethylpropyl)quinazolin-4(3H)-one 38 (Q(4)NHOAc) with the same beta-substituted styrenes.An explanation for these observations is offered based on a tighter, more symmetrical transition state for the aziridination of styrenes bearing the more electron-withdrawing beta-substituents and is supported by SCF calculations.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

The two pseudoenantiotopic N-acyl groups of enantiopure 3-[N-(3-m-acetoxyphenylpropanoyl)-N-(3-phenylpropanoyl)amine]-2-isopropylquinazolin-4(3H)-one 7 each react with a different enantiomer of 2-methylpiperidine giving rise to efficient parallel kinetic resolution (ee > 95%).

The title compounds diacylaminoquinazolinones (DAQs) are enantioselective acylation agents for amines and a detailed study of their stereostructures was undertaken with the aim of understanding how this enantioselectivity arises. The N–N bond in these DAQs is a chiral axis. Even where both N-acyl groups are (S)-2-acetoxypropanoyl, the N–N bond is still a chiral axis because in the most stable conformation of the planar imide moiety, one exo/endo orientation of the carbonyl groups is much preferred over the alternative (endo/exo) as revealed by NMR spectroscopy. A conformational preference within the 2-acetoxypropanoyl grouping accounts for the presence of a single exo/endo conformation in solution for some of these DAQs (see above) but an interconverting exo/endo⇌endo/exo mixture for others. Where a single exo/endo conformation is present in solution, evidence is presented that this closely resembles the X-ray determined crystal structure. A mechanism for the second acylation step to form these DAQs is proposed, which involves preliminary O-acylation of the 3-(monoacylamino)quinazolinone.

Aziridination of cyclopentadiene and cyclohepta-1,3-diene with (S)-3-acetoxyamino-2-(3-hydroxy-2,2-dimethylpropyl)quinazolin-4(3H)-one 6 (Q1NHOAc) in the presence of titanium(IV) tert-butoxide in dichloromethane takes place highly diastereoselectively: X-ray structure determinations show that the preferred sense of diastereoselectivity in both cases is the same as that previously found for aziridination of butadiene with 6. Aziridination of cyclohexa-1,3-diene with 6 was less diastereoselective in dichloromethane solution but highly diastereoselective in acetonitrile: in this solvent two diastereoisomeric cis-4-(Q1-amino)cyclohexen-3-ols 27 and 28 were also obtained as by-products. The same two amino alcohols were obtained by ring-opening of the aziridine with acid and were each converted into Q1-free oxazolidinones having optical rotations which were similar in magnitude but opposite in sign.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

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).

The presence of the Q group in ring-opening reactions of N-(Q)-aziridines 3, 4, 5 and 6 has been found to be advantageous in the following ways, (i) nucleophilic ring-opening by cuprate or by azide with inversion of configuration is assisted by the electron-withdrawing character of the Q group, (ii) ring-opening of aziridines 5 or 6 to the corresponding alcohols 36 and 23 with retention of configuration can be accomplished by participation of the Q group: the Q carbonyl oxygen becomes the hydroxy oxygen in the alcohol product, (iii) the combined effects of the electron-withdrawing Q group and ring strain allow preparation of individual aziridine N-invertomers 3 and 4 whose ring-opening with hydrogen chloride in dichloromethane proceeds with complementary stereochemistry. The Q group is also believed to be involved in ring-opening of aziridines 5 and 6 mediated by samarium(III) nitrate hexahydrate with predominant retention of configuration. Reductive removal of the Q group from these ring-opened products gave chirons 12, 19 and 21.

Four diastereoisomeric 3-diacylaminoquinazolinones 8a-d have been separated and identified by X-ray structure determinations on three of them: their stoichiometric reactions with alpha-phenylethylamine and with 2-methylpiperidine (2 equiv. of amine) gave the corresponding N-(2-acetoxypropanoyl)amine and unreacted amine in high diastereomeric/enantiomeric excess.

Whereas 3-diacylaminoquinazolin-4(3H)-ones (DAQs) have been previously shown to undergo rapid exo/endo–endo/exo conformational interconversion of their imide carbonyl groups, the title DAQs are believed to exist in one single exo/endo form and consequently their N–N bonds are chiral axis: one of these DAQs, substituted with a diphenylmethyl group on the Q-2 position, reacts preferentially with one enantiomer of racemic 2-methyl-piperidine at the 2-acetoxypropanoyl imide carbonyl group (ee 94%).

Aziridination of phenyl-substituted allylic alcohol 10 with 3-acetoxyaminoquinazolinone 3 (Q(1)NHOAc) and with 22 (Q(2)NHOAc) has been studied. The diastereoselectivity of these reactions is markedly changed by carrying them out in the presence of aqueous sodium hydrogen carbonate solution and under these conditions aziridinations of 10 and of its ester analogue 5 with Q(2)NHOAc give the same magnitude and sense of diastereoselectivity (with Ph=CO2Me). An explanation for these changes in diastereoselectivity is offered based upon differences in the nature of the hydrogen bonding in the transition states for aziridination of 10 with and without the presence of acetic acid.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

The effects of TFA on the competitive reactions of 3-acetoxyaminoquinazolinones 2 and 10 with methyl acrylate and with tert-butyl acrylate are interpreted as supporting a change in transition state geometry from one where (Q) C=O/ (ester)C=O overlap 7b is replaced by (Q)C=N+H/(ester)C=O overlap 7c (Q = quinazolinone). Aziridinations of methyl or tert-butyl acrylate using 2-trifluoromethyl-substituted 3-acetoxyaminoquinazolinones:20 and 21 take place with (Q) C=N/(ester)C=O overlap;22 even in the absence of TFA.

In aziridinations of β-substituted styrenes ( 4 ), ( 5 ) and ( 6 ) with the enantiopure 3-acetoxyaminoquinazolinone ( 1 ), diastereoselectivity (dr) increases from 5:1 (for ( 9 ) to 10:1 (for ( 10 ) to ∼20:1 (for ( 11 )): changes in transition state geometry which account for this increase are rationalised using Frontier Orbital Theory.

The presence of the quinazolin-4(3H)-one ring (Q∗) in N-(Q∗)-aziridines facilitates ring-opening by nucleophiles: removal of the Q∗ group from enantiopure ring-opened products gives useful chirons.

The presence of the quinazolin-4(3H)-one (Q) ring in 1-(Q)-2-vinylaziridine (2) can be used to control the stereochemistry of the 3-membered ring-opening; participation by the quinazolinone carbonyl oxygen brings about ring-opening with retention of configuration. (C) 1998 Elsevier Science Ltd. All rights reserved.