3-Di-[(S)-2-acetoxypropanoyl] aminoquinazolin-4(3H)-ones: Stereostructure and application in kinetic resolution of amines

Article abstract of DOI:10.1016/S0040-4039(00)00139-8

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%). (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00139-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 2243–2246
3-Di-[(S)-2-acetoxypropanoyl]aminoquinazolin-4(3H)-ones:
stereostructure and application in kinetic resolution of amines
Abdullah G. Al-Sehemi, Robert S. Atkinson,∗ John Fawcett and David R. Russell
Department of Chemistry, Leicester University, Leicester, LE1 7RH, UK
Received 9 December 1999; accepted 18 January 2000
Abstract
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%). © 2000 Elsevier Science Ltd. All
rights reserved.
3-Diacylaminoquinazolinones (DAQs) e.g. 1 are highly chemoselective acylating agents for primary
amines over secondary amines and, in particular, for the less hindered of two secondary amines.1 They are
readily available by acylation of the corresponding 3-aminoquinazolinones; since the second acylation is
slower than the first, DAQs bearing two different acyl groups are readily prepared.2
When the two acyl groups on the exocyclic nitrogen are different, the N–N bond is a chiral axis
since the quinazolinone and imide-containing planes are orthogonal and no complete rotation around
the N–N bond occurs at room temperature. The presence of a chiral centre in a substituent on the 2-
position of the quinazolinone, or in one of the acyl groups, gives rise to diastereoisomeric DAQs e.g.
∗
Corresponding author.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00139-8
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2a/2b: interconversion between these separated diastereoisomers (atropisomers) takes place on heating
in toluene at 100°C over 1 h (∆G# 121 kJ mol−1) by rotation around the N–N bond.2
Evidence for the exo/endo conformation for the imide moiety in DAQ 1 follows from the NMR
spectrum of DAQ 3. At room temperature, the acetyl methyl signals are present as a broadened singlet:
2
at −85°C in H6-acetone this singlet has separated into two singlets of equal intensity. At this low
temperature also, the methylene protons of the ethyl group become diastereotopic because the N–N bond
is now a chiral axis. The exo/endo conformation is also that adopted in crystal structures of these DAQs.2
The chemoselectivity shown by achiral DAQ 1 referred to above has a stereoselective counterpart when
the chiral DAQ is used in enantiopure form. Thus DAQ 4 prepared by successive acylation of the 3-
aminoquinazolinone with (S)-2-acetoxypropanoyl chloride and isobutanoyl chloride, was separated into
its diastereoisomers by chromatography. Reaction of one enantiopure diastereoisomer with racemic 1-
phenylethylamine gave a 3·6:1 ratio of amide diastereoisomers 5 and hence this DAQ 4 diastereoisomer
reacts preferentially with one enantiomer of the amine bringing about partial kinetic resolution.2
The use of an enantiopure DAQ e.g. 6a bearing two identical chiral acyl substituents would be
advantageous for kinetic resolution of amines since separation of diastereoisomers would not be required.
However, since exo/endo–endo/exo imide interconversion 6az6b is expected to be fast on the timescale
of the reaction with amines, the N–N bond is not a chiral axis (6a and 6b have opposite configurations
for their N–N chiral axes). Though kinetic resolution of chiral racemic amines with 6a/6b might still be
feasible, our experience is that the presence of the N–N bond as a chiral axis is required for high levels
of enantioselectivity.3
The three DAQs 7, 8 and 9 have been prepared by diacylation of the appropriate 3-aminoquin-
azolinone with (S)-2-acetoxypropanoyl chloride and pyridine: unexpectedly, the formation of DAQ 9
proceeded faster and in better yield (87%) than that of DAQs 7 or 8.
Crystal structures4 of DAQs 7 and 9 (Fig. 1) show the expected (S)-configuration at both chiral centres
in the two N-acyl groups. The exo/endo conformation for the imide is present in each case and this is
expected to be the preferred conformation in solution also.

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Fig. 1. The molecular structures of 7 and 9: H atoms on chiral centres are shown with open bonds, all other H atoms are omitted
for clarity
The NMR spectrum of DAQ 8 shows the CH(OAc)CH3 signals as two quartets at δ 4·48 and 5·92
ppm and the corresponding methyl proton signals CH(OAc)CH3 at δ 1·10 and 1·60 ppm. Likewise, the
corresponding signals for DAQs 7 and 9 are comparably different in chemical shift. In contrast to the
temperature dependence of the NMR spectrum of DAQ 3, there was no change or even broadening of
the CH(OAc)CH3 signals in DAQs 7 and 8 down to −50°C in CDCl3. Thus, fast exo/endo–endo/exo
conformational interconversion of the imide in DAQs 7 and 8 in solution at room temperature is not
occurring.5
In the equilibrium DAQ 6az6b it is important to note that, because of the absence of N–N bond
rotation, the two species are diastereoisomeric and hence could differ in energy. The NMR spectra of
DAQs 7, 8 and 9 above are consistent with the presence of only one diastereoisomeric form in solution,
presumably that present in the crystal form in 7 and 9. If these exo/endo conformations are also the only
reacting ones then selective reaction with one enantiomer of a racemic amine is in prospect because the
N–N bonds are chiral axis (contrast 6ay6b above).
Even under conditions of stoichiometry, DAQ 7 (1 equiv.) reacts with 2-methylpiperidine (2 equiv.)
in dichloromethane at 0°C to give a 5:1 ratio of diastereoisomers of N-[(S)-2-acetoxypropanoyl]-2-
methylpiperidine (76%): reaction of DAQ 9 with 2-methylpiperidine under the same conditions gave N-
[(S)-2-acetoxypropanoyl]-2-(S)-methylpiperidine 10 (86%) as the major product (dr 33:1) corresponding
to an ee of 94%.6 Reaction of DAQ 9 with excess racemic 1-phenylethylamine gave an 8:1 ratio of amide
diastereoisomers (ee 78%).7 Unreacted amine is removed in the work-up by extraction with hydrochloric
acid and amide product separated from the (re-usable) N-monoacyl-quinazolinone by chromatography:
modification of the DAQ used to avoid the necessity for this chromatography is under investigation.
Acknowledgements
We thank the Ministry of Education in Saudi Arabia for funding (to A.G.Al-S).
References
1. Atkinson, R. S.; Barker, E.; Sutcliffe, M. J. J. Chem. Soc., Chem. Commun. 1996, 1051.

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2. Atkinson, R. S.; Barker, E.; Edward, P. J.; Thomson, G. A. J. Chem. Soc., Perkin Trans. 1 1996, 1047: see, previous paper in
this issue, Al-Sehemi, A. G.; Atkinson, R. S.; Fawcett, J.; Russell, D. R. Tetrahedron Lett. 2000, 41, 2239.
3. We have prepared N-[(S)-2-acetoxypropanoyl]-N-acylaminophthalimides (which have no chiral axis) and have obtained no
kinetic resolution in reaction with amines.
4. X-Ray crystallography data for 7: C19H21N3O7, M=403.4, orthorhombic, space group C2221, a=10.317(3), b=12.483(3),
c=31.820(7) Å, V=4098(2) Å3, Z=8, µ(Mo-Kα)=0.101 mm−1, 3659 reflections measured, 3242 unique (Rint=0.028) which
were all used in calculations. Final R1=0.051 and wR2=0.128 (all data). Data for 9: C31H29N3O7, M=555.57, orthorhombic,
space group P212121, a=11.315(3), b=14.210(2), c=17.368(5) Å, V=2792(1) Å3, Z=4, µ(Mo-Kα)=0.095 mm−1, 3891
reflections measured, 3692 unique (Rint=0.029) which were all used in calculations. Final R1=0.102 and wR2=0.309 (all data).
Data were measured on a Siemens P4 diffractometer at 190K using graphite monochromated Mo-Kα radiation (λ=0.7107 Å)
using an ω scan technique. Three standard reflections monitored every 100 scans showed no significant variation in intensity,
the reflections were corrected for Lorentz and polarisation effects. The structures were solved by direct methods and refined
by full-matrix least squares on F2 using the program SHELXTL [G. M. Sheldrick, SHELXTL version 5.1, Bruker AXS
Inc., Madison, WI, 1997]. The absolute configurations of the compounds were established by the refinement of the Flack
parameters. All hydrogen atoms were included in calculated positions (C–H=0.96 Å) using a riding model. All non-hydrogen
atoms were refined with anisotropic displacement parameters.
5. The NMR spectrum of DAQ 9 is temperature dependent but is not compatible with fast exo/endo–endo/exo interconversion
at room temperature.
6. Reaction of DAQ 9 (1 equiv.) with racemic 2-propylpiperidine (coniine) (4 equiv.) also gave high enantioselectivity (ee 95%)
(yield 70%).
7. The faster reacting enantiomers of the amines with DAQ 9 [(S) for 2-methylpiperidine and (R) for 1-phenylethylamine] were
identified by NMR comparison of the major diastereoisomers formed with authentic samples prepared from reaction of each
enantiomer of the respective amine with (S)-2-propanoyl chloride.