Acyl transfer of 8-acetoxy-2-oxazolinylquinoline assisted by hydrogen bonding formation

Article abstract of DOI:10.1016/S0040-4039(01)02329-2

A significant acceleration of acyl transfer has been achieved on 8-acetoxy-2-oxazolinylquinoline in the presence of benzylamine. Comparison of the aminolysis by the new acylating reagent with that of 8-acetoxyquinoline and 8-acetoxyquinoline-2-carbonitrile has been carried out. The results of these experiments suggest that the proximity of a supplementary basic atom to the ester group increases the participation effect of the basic site mainly by formation of a possible second hydrogen bond. The association constant of benzylamine into the basic cavity of 8-methoxy-2-oxazolinylquinoline (K_a=80 M^-1) has been measured by ¹H NMR titration experiments.

Full text of DOI:10.1016/S0040-4039(01)02329-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 1027–1029
Acyl transfer of 8-acetoxy-2-oxazolinylquinoline assisted by
hydrogen bonding formation
Laurent Hortala,a Christina Moberg,b Vincent Levacher,a Jean Bourguignona and Georges Dupasa,*
aLaboratoire de Chimie Organique Fine et He´te´rocyclique UPRES-A 6014 IRCOF-INSA, BP 08, F-76131 Mont Saint Aignan
Cedex, France
bDepartment of Chemistry, Organic Chemistry, Royal Institute of Technology, SE-100 44 Stockholm, Sweden
Received 17 October 2001; accepted 6 December 2001
Abstract—A significant acceleration of acyl transfer has been achieved on 8-acetoxy-2-oxazolinylquinoline in the presence of
benzylamine. Comparison of the aminolysis by the new acylating reagent with that of 8-acetoxyquinoline and 8-acetoxyquinoline-
2-carbonitrile has been carried out. The results of these experiments suggest that the proximity of a supplementary basic atom to
the ester group increases the participation effect of the basic site mainly by formation of a possible second hydrogen bond. The
association constant of benzylamine into the basic cavity of 8-methoxy-2-oxazolinylquinoline (Ka=80 M−1) has been measured by
1H NMR titration experiments. © 2002 Elsevier Science Ltd. All rights reserved.
8-Acetoxyquinolines are well known to catalyse their
own ester aminolysis via intramolecular participation of
the neighboring basic nitrogen atom, as indicated in
Scheme 1.
tion of the quinoline nitrogen atom via an additional
basic complexing center.
A molecular modeling study showed that an oxazoline
moiety in the 2-position of the 8-acetyloxyquinoline
structure was well adapted to display a new basic center
close enough to the ester function. Moreover, from this
study, we could observe the binding of benzylamine via
two hydrogen bonds. The intermolecular complex
formed would place the amine nitrogen close to the
carbonyl group of the ester function with a distance of
A large number of kinetic studies have been reported
by Bruice and co-workers1 showing the high reactivity
of 8-acetoxyquinoline towards primary and secondary
amines. The acetylation of amino acids has also been
investigated.2 8-Acetoxyquinoline has also displayed
high acetylation yields when grafted on a polymer.3 As
discussed in the literature, if the formation of a vicinal
hydrogen bonding is responsible for the facile ester
aminolysis, then it might be possible to improve the
kinetics of the aminolysis by enlarging the basic site.
Up until now, no structural modification has been
developed to enhance this basic catalytic effect. We
herein wish to disclose a novel derivative of the 8-ace-
toxyquinoline structure able to increase the participa-
,
roughly 3 A (Fig. 1).
This new potential acylating agent has been synthesized
in only two steps with good yields. In a first step, the
oxazoline has been formed in a one-pot reaction,4 by
condensation of (R)-phenylglycinol with 8-hydroxy-
quinoline-2-carbonitrile (2) according to Breslow’s
procedure.5 In
a
second step, 8-hydroxy-2-oxa-
Scheme 1.
* Corresponding author.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)02329-2

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L. Hortala et al. / Tetrahedron Letters 43 (2002) 1027–1029
Scheme 3.
Figure 1. The hydrogen bonding complex between 8-acetoxy
2-oxazolinylquinoline and benzylamine has been minimized
using the Cerius2® package. The hydrogen bond between
,
NH···N (quinoline) is 2.1 A long and NH···N (oxazoline) is
,
1.9 A long.
zolinylquinoline was further easily acylated with acetic
anhydride6 (Scheme 2).
Figure 2. The geometries were first optimized with the
Cerius2® package. Ab initio calculations were then performed
with Gaussian-94 and the STO-6-31G basis set.
The complexation ability of benzylamine via hydrogen
bonding in the basic cavity was confirmed by a proton
titration experiment7 with 8-methoxy-2-oxazolinyl-
quinoline 5. Indeed, this methylated analogue of 4
permitted blocking of the acylating position, while
preserving the basic center. An association constant of
80 M−1 was measured. This value of the association
constant is in good agreement with a two binding
points process8 with benzylamine (Scheme 3).
The reactivities of this new compound and of 8-ace-
toxyquinoline (1) were compared in order to evaluate
their acylating potentialities toward benzylamine. The
aminolysis reactions have been carried out at room
temperature and the evolution of the reactions moni-
1
tored by H NMR.8 As can be seen from Fig. 3, the
acylating agent 4 is much more efficient than 8-
acyloxyquinoline and no significant evolution of the
reaction could be observed with 8-acetoxynaphthalene.
The significant acceleration observed is most probably
due to the formation of an extra hydrogen bond during
the reaction process. However, the electron-withdraw-
ing effect of the oxazoline group in the 2-position
cannot be discarded since it would stabilize the pheno-
late leaving group.
Figure 3. Benzylacetamide formation monitored by proton
NMR spectroscopy.
STO-6-31G level of theory (Fig. 2) on pyridine-2-car-
bonitrile (6) and 2-pyridyloxazoline 7.9 Moreover, we
could verify by a molecular modeling study on quino-
line-2-carbonitrile that the nitrile group, because of its
linear geometry, did not allow any additional hydrogen
bonding. So, in order to evaluate the actual role of the
above-mentioned electronic effect, the aminolysis of
8-acyloxyquinoline-2-carbonitrile (8) was performed
under the same experimental conditions. The corre-
sponding results are depicted in Fig. 3.
It could be reasonably presumed that the electron-with-
drawing effect of a nitrile group is more efficient than
that of an oxazolinyl moiety. This assumption was
confirmed by an ab initio MO calculation at the HF/
Scheme 2. Reagents and conditions: (i) R-Phenylglycinol, cat. CuCl2, 100°C/1 h, 90%; (ii) EDTA/K2CO3; (iii) Ac2O/reflux/1 h,
100%.

L. Hortala et al. / Tetrahedron Letters 43 (2002) 1027–1029
1029
Firstly, by facilitating attack of the primary amine by
pre-complexation via hydrogen bonding into the basic
pocket, as shown by the above molecular modeling
study and the value of the association constant. This
type of complexation could enhance the nucleophilicity
of the amine nitrogen, as recently demonstrated by
Philp et al.9
Secondly, by increasing the stability of the tetrahedral
intermediate as proposed in Scheme 4.
To conclude, the synthesis and the aminolysis study of
a new kind of acylating agent has been performed. This
agent exhibited higher reactivity towards benzylamine
than 8-acetoxyquinoline and 8-acetoxyquinoline-2-car-
bonitrile.
The results of aminolysis studies tend to prove that the
formation of an additional hydrogen bond is mainly
responsible for the high acceleration observed. A com-
plementary study using an NMR titration method sug-
gested that benzylamine can be pre-complexed via
hydrogen bonding into the basic pocket with an associ-
ation constant of about 80 M−1. We are presently
studying the chiral discrimination properties of receptor
5 by hydrogen bonding complexation of chiral amines
with the view to developing a new resolution process of
primary amines using this class of acylating agents and
quinoline analogues.
Scheme 4.
The reaction has been run in CDCl3 using an excess of
5 equivalent (Ci=0.085 M) of benzylamine for 1 equiv-
alent (Cr=0.017 M) of acylating agent. Conversion rate
x was determined by integration of the methyl protons
of benzylacetamide formed and methyl ester consumed.
References
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6721.
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1982, 9, 709.
Calculation of the rate constants shows that, in spite of
the stronger electron withdrawing power of the nitrile
group, 8-acetyloxy-2-oxazolinylquinoline 4 (k=0.21
mol−1 l min−1) still reacts five times faster than 8
(k=0.04 mol−1 l min−1). This last result suggests that
the formation of a second hydrogen bond is more
important than an electron-withdrawing effect in the
2-position of quinoline.
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From the topology of that new acylating agent, display-
ing a neighboring complexing center to the ester group,
we could explain this substantial acceleration by taking
into account two types of considerations.
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Org. Lett. 2000, 2, 1365.