Kinetic resolution of amines by acylation using 3-diacylaminoquinazolin- 4(3H)-ones

Article abstract of DOI:10.1039/a907970j

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

Full text of DOI:10.1039/a907970j

Kinetic resolution of amines by acylation using
3-diacylaminoquinazolin-4(3H)-ones
Abdullah G. Al-Sehemi, Robert S. Atkinson, John Fawcett and David R. Russell
Department of Chemistry, Leicester University, Leicester, UK LE1 7RH. E-mail: vow@le.ac.uk
Received (in Cambridge) 4th October 1999, Accepted 16th November 1999
Four diastereoisomeric 3-diacylaminoquinazolinones 8a–d
have been separated and identified by X-ray structure
determinations on three of them: their stoichiometric
reactions with a-phenylethylamine and with 2-methylpiper-
idine (2 equiv. of amine) gave the corresponding N-
(2-acetoxypropanoyl)amine and unreacted amine in high
diastereomeric/enantiomeric excess.
3-Diacylaminoquinazolinones (DAQs), e.g. 1, are highly se-
lective acylating agents for primary amines in the presence of
Scheme 1
secondary amines and for the less hindered of two secondary
amines.1 Recently the N,N-diacetamide 2 has been claimed to be
even more chemoselective than DAQ 1 as an acetylating agent:
a 1+1 mixture of pyrrolidine and piperidine (DpKa = 0.01)
reacts with 2 to give a 15+1 ratio of the corresponding N-
acetylated amines.2
ride (Scheme 2) gave four DAQ diastereoisomers 8a–d in order
of their elution on chromatography (see below). The major
diastereoisomer 8b was separated by crystallisation (35%) after
flash chromatography to remove unreacted mono-acylquinazo-
linone (MAQ) and pure samples of the other three, 8a (5%), 8c
(7%) and 8d (26%), were obtained by separation using a
chromatotron.
X-Ray crystal structure determinations of DAQs 8b and 8c
(Fig. 1) showed them to have the expected (S)-configuration at
their a-acetoxypropanoyl chiral centres but different configura-
tions at their N–N chiral axes.‡ Heating (CDCl3, 60 °C, 42 h)
interconverted 8b and 8c and gave a 5+4 ratio respectively at
equilibrium, presumably as a result of rotation around the N–N
bond: no interconversion with 8a or 8d occurred.
Diastereoisomers 8a and 8d arise from epimerisation at the
a-acetoxypropanoyl centre as shown by the (R)-configuration
in the X-ray crystal structure of 8d (Fig. 1).‡ Interconversion of
8a and 8d by heating (CDCl3, 60 °C, 13 h) gave a 6+1 ratio at
equilibrium, respectively: no interconversion with 8b and 8c
occurred in this equilibrium.
Although in their crystal structures DAQ 8b–d all have the
usual4 exo/endo conformation for their imides, 8b and 8c have
their a-acetoxypropanoyl groups endo and the isobutanoyl
group exo whereas 8d has the positions of these two groups
reversed.
We find that these DAQs 8a–d are enantioselective acylating
agents for racemic amines. Thus DAQ 8c (1 equiv.) reacts with
a-phenylethylamine (2 equiv.) in CH2Cl2 at 5 °C to give
(2R,2AS)-N-(-2-acetoxypropanoyl)-a-phenylethylamine [77%
based on (R)-a-phenylethylamine, 88% de] by NMR compar-
ison with authentic samples of both diastereoisomers: the
recovered S enantiomer of the amine [90% based on (S)-a-
phenylethylamine] was of 91% ee from its specific rotation
(Scheme 3).
The DAQs 3, 4 and 5 were available to us by acetylation of
the corresponding 3-aminoquinazolinones3 and, when reacted
with a mixture of pyrrolidine and piperidine (1 equiv. each) at
0 °C in CH2Cl2 gave the ratios of the corresponding amides
shown in Scheme 1. Unexpectedly, the chemoselectivity
increases as the substituent R on the chiral centre decreases in
size from But ? Me with a 20+1 ratio for methyl.†
Since DAQs 3, 4 and 5 are enantiopure we were particularly
interested in a greater potential advantage which their use
offered over that of e.g. 2, namely as enantioselective
acetylating agents.4 However, reaction of DAQ 3 (1 equiv.)
with racemic 2-methylpiperidine (2 equiv.) gave a sample of
recovered amine having zero optical rotation and hence there is
no kinetic resolution in this acetylation.
For 3-aminoquinazolinones N,N-disubstituted with different
acyl groups, we have previously shown that the N–N bond is a
chiral axis: in DAQ 6 the presence of two chiral elements gives
rise to diastereoisomers with a barrier DG# = 121 kJ mol21 for
their interconversion by rotation around the N–N bond.4
Successive acylation of enantiopure 3-aminoquinazolinone
73 with (S)-2-acetoxypropanoyl chloride and isobutanoyl chlo-
Scheme 2
Chem. Commun., 2000, 43–44
This journal is © The Royal Society of Chemistry 2000
43

occurs in the second acylation step.¶ An alternative, more
stereoselective route to these DAQs was to carry out the second
acylation using the lithium salt of the MAQ. Thus reaction of
the lithium salt of MAQ 11 with (S)-2-acetoxypropanoyl
chloride gave DAQ 8c (71%) and 8a (8%) (based on recovered
starting material), i.e. with less epimerisation than previously.
Kinetic resolution is usually carried out in the presence of
excess of the substrate to maximise enantiopurity in its
derivatised enantiomer. Even under the most testing conditions
of stoichiometry as in Scheme 3, DAQ 8c delivers both
derivatised and unreacted enantiomers of the substrate with high
enantioselectivity.
We thank the Ministry of Education, Saudi Arabia for
funding (to A. G. Al-S).
Notes and references
† This increase may be related to the preference for a defined conformation
around the C–OSi bond in the (Q) 2-substituent in 3 but not in 4 or 5 (see
R. S. Atkinson, M. P. Coogan and I. S. T. Lochrie, Tetrahedron Lett., 1996,
37, 5179.
‡ Crystal data for 8b: C27H41N3O6Si, M = 531.72, orthorhombic, space
group P212121, a = 10.146(1), b = 13.296(2), c = 22.618(3) Å, V =
3051.4(7) Å3, Z = 4, m(Mo-Ka) = 0.118 mm21, 3845 reflections measured,
3639 unique (Rint = 0.013) which were all used in calculations. Final R1
=
0.052 and wR2 = 0.114 (all data). For 8c: C27H41N3O6Si, M = 531.72,
orthorhombic, space group P212121, a = 9.391(2), b = 13.554(6), c =
23.908(13) Å, V = 3043(2) Å3, Z = 4, m(Mo-Ka) = 0.118 mm21, 3756
reflections measured, 3592 unique (Rint = 0.035) which were all used in
calculations. Final R1 = 0.102 and wR2 = 0.309 (all data). For 8d:
C27H41N3O6Si, M = 531.72, orthorhombic, space group P212121, a =
12.152(9), b = 13.170(7), c = 18.293(9) Å, V = 2928(3) Å3, Z = 4, m(Mo-
Ka) = 0.118 mm21, 3666 reflections measured, 3455 unique (Rint = 0.155)
which were all used in calculations. Final R1 = 0.044 and wR2 = 0.099 (all
data). Data were measured on a Siemens P4 diffractometer at 190 K using
graphite monochromated Mo-Ka radiation (l = 0.7107 Å) using an w-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. The absolute configurations of
the compounds were established by the known configuration at the silyloxy
substituted carbon atom. All examined crystals of 8c diffracted weakly; to
preserve an observed data to variable ratio of 6+1 the 13 most closely
isotropic atoms were constrained to be isotropic. All hydrogen atoms were
included in calculated positions (C–H = 0.96 Å) using a riding model.
CCDC 182/1486. See http://www.rsc.org/suppdata/cc/a9/a907970j/ for
crystallographic data in .cif format.
Fig. 1 Molecular structures of (a) 8b, (b) 8c and (c) 8d showing atom
labelling schemes and 30% probability displacement parameters. H atoms at
chiral centres are shown with dashed bonds, all other H atoms are omitted
for clarity.
§ A mixture of amide diastereoisomers 9a and 9b was prepared by reaction
of (S)-2-acetoxypropanoyl chloride with racemic 2-methylpiperidine. An
authentic sample of amide 9b was prepared from (R)-2-methylpiperidine,
[a]D (HCl salt) 8.9 (c 2, EtOH), itself prepared from the racemic amine by
resolution using (R)-mandelic acid.
¶ Significantly, the MAQ recovered from the reaction in Scheme 2 was also
found to be a mixture of two diastereoisomers, epimeric at the 2-acetoxy-
propanoyl chiral centre.
Scheme 3
Reaction of DAQ 8c (1 equiv.) with racemic 2-methylpiper-
idine 10 (2 equiv.) in CH2Cl2 at 5 °C for 24 h gave, after
chromatography, monoacylquinazolinone (MAQ) 11 (77%)
and (2S,2AS)-1-(2A-acetoxypropanoyl)-2-methylpiperidine 9a
(79%) (Scheme 3) whose diastereopurity (de) as measured by
NMR spectroscopy was 95%. The unreacted 2-methylpiper-
idine enantiomer was recovered from the crude reaction mixture
by extraction with HCl (2 M) and derivatised by reaction with
(S)-2-acetoxypropanoyl chloride to give 9b (81%) of 89% de: at
400 MHz and 50 °C the OCOCH3 signals of diastereoisomers
9a and 9b are well separated.§
1 R. S. Atkinson, E. Barker and M. J. Sutcliffe, Chem. Commun., 1996,
105.
2 Y. Murakami, K. Kendo, K. Miki, Y. Akiyama, T. Watanabe and Y.
Yokoyama, Tetrahedron Lett., 1997, 38, 3751.
3 R. S. Atkinson, A. P. Ayscough, W. T. Gattrell and T. M. Raynham,
J. Chem. Soc., Perkin Trans. 1, 1998, 2783.
4 R. S. Atkinson, E. Barker, P. J. Edwards and G. A. Thomson, J. Chem.
Soc., Perkin Trans. 1, 1996, 1047.
Since DAQ 8b was recovered unchanged when re-subjected
to the conditions of the second acylation in Scheme 2, it appears
that epimerisation at the 2-acetoxypropanoyl chiral centre
Communication a907970j
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Chem. Commun., 2000, 43–44