A mild method for ring-opening aminolysis of lactones

Article abstract of DOI:10.1016/S0040-4039(01)00196-4

A mild and general method for lactone aminolysis is reported. Sodium 2-ethylhexanoate (NaEH) is found to serve both as a base and a catalyst in aminolysis of a variety of lactones by benzylamine hydrochloride. The nearly neutral pH conditions make this method applicable to many acid/base sensitive substrates.

Full text of DOI:10.1016/S0040-4039(01)00196-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 2439–2441
A mild method for ring-opening aminolysis of lactones
Wenming Liu, David D. Xu,* Oljan Repicˇ and Thomas J. Blacklock
Process R & D, Chemical and Analytical Development, Novartis Institute for Biomedical Research, 59 Route 10, East Hanover,
NJ 07936, USA
Received 5 October 2000; revised 15 January 2001; accepted 30 January 2001
Abstract—A mild and general method for lactone aminolysis is reported. Sodium 2-ethylhexanoate (NaEH) is found to serve both
as a base and a catalyst in aminolysis of a variety of lactones by benzylamine hydrochloride. The nearly neutral pH conditions
make this method applicable to many acid/base sensitive substrates. © 2001 Elsevier Science Ltd. All rights reserved.
Lactone aminolysis, apparently a simple transforma-
tion, generally requires rather harsh conditions, such as
high temperature1 or strong alkali–metal catalysts.2
These conditions pose significant limitations to their
applications. Furthermore, a large excess of amines is
frequently used to ensure proper conversion and reac-
tion rate,3 making the direct aminolysis uneconomical
especially when the amines are not readily available.
aminolysis and the possibility of utilizing the amine
HCl salt directly, we came upon an earlier report from
our group.4 Prasad et al. reported that sodium 2-ethyl-
hexanoate (NaEH) can be used as an effective organic-
soluble acid scavenger in amine acylations with acid
chloride. We found that, in addition to being an effec-
tive acid scavenger, NaEH also offered a dramatic
accelerating effect for lactone aminolysis by the HCl
salts of primary amines.
Recently, we encountered a challenging aminolysis of a
sugar-derived lactone by a primary amine: both the
amine and the lactone were products of expensive
multi-step syntheses. Additionally, the lactone was
unstable at slightly elevated pHs and the amine could
not be easily isolated in its free base form. In search for
neutral and mild conditions to carry out this lactone
The catalytic effect of NaEH in lactone aminolysis is
clearly demonstrated in using benzylamine and g-
decanolactone as the model system (Table 1). No
aminolysis was observed when g-decanolactone was
treated with benzylamine at ambient temperature in
tetrahydrofuran (entry 1). Triethylamine showed no
Table 1. Aminolysis of g-decanolactone with benzylamine or benzylamine hydrochloride
OH
THF, RT, 17-24 h
H
N
H3C
Ph
H3C
O
O
H2N
Ph
1
O
or
ClH3N
Ph
1-HCl
Entry
Reactant
Additive (equiv)
Yield (%)a
1
2
3
4
5
1
1
None
0
0
0
10
83
Et3N (2.5)
Et3N (2.5)
NaEH (2.5)
NaEH (2.5)
1-HCl
1
1-HCl
a Isolated yields.
Keywords: lactone; aminolysis; sodium 2-ethylhexanoate.
* Corresponding author. E-mail: david.xu@pharma.novartis.com
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00196-4

2440
W. Liu et al. / Tetrahedron Letters 42 (2001) 2439–2441
observable effect on the aminolysis when either the free
base or the HCl salt of benzylamine was used (entries 2
and 3). On the other hand, NaEH demonstrated small
but discernible catalytic effect when free benzylamine
was used, as indicated by the 10% isolated yield of the
product amide (entry 4). However, NaEH showed a
dramatic catalytic effect when benzylamine hydrochlo-
ride was used directly, the product amide was isolated
in 83% yield (entry 5)!
ing group (entry 3). Similarly, lactone 5a with a TBS
and an acetonide protecting group was converted to its
benzyl amide in excellent yield (entry 4). The sterically
hindered bicyclic lactone 6a failed to give the product
amide at room temperature (entry 5), but the desired
amide 6b could be generated in good yield after the
reaction was heated at 70°C for 8 h (entry 6). Both
tetrahydropyranyl and t-butyldimethylsilyl protecting
groups remained intact under these conditions, again
demonstrating the mildness of this aminolysis method.
The general applicability of this lactone aminolysis
method is demonstrated in Table 2. A variety of struc-
turally distinct lactones were successfully converted to
the corresponding amides by benzylamine hydrochlo-
ride in the presence of NaEH. Compared with g-lac-
tone, b- and d-lactones were much more reactive under
these conditions (entries 1 and 2). The mildness of our
method was demonstrated by the aminolysis of 4a,
which was shown to be both acid and base sensitive. It
readily underwent b-elimination under basic conditions,
while the acetonide protecting group rearranged from
1,2- to 1,3-dioxane under acidic conditions. Our condi-
tions effected the formation of amide 4b smoothly at
ambient temperature without any noticeable decompo-
sition of 4a or the scrambling of the acetonide protect-
While our limited data do not allow us to offer a
definitive mechanism for the significant accelerating
effect of NaEH in lactone aminolysis, we speculate that
the acceleration arises from concerted actions of the
base (NaEH) and its conjugated acid (EHA) on both
the amine and the lactone.5 We are currently in the
process of elucidating the mechanism of this reaction
and utilizing this method to other examples.
In summary, a mild and general lactone aminolysis
method is presented. NaEH has been shown to signifi-
cantly accelerate the aminolysis of lactones with the
HCl salts of primary amines. The conditions are close
Table 2. Lactone aminolysis with benzylamine hydrochloride (1.5 equiv.) and NaEH (2.5 equiv.) in tetrahydrofurana
a
The reaction was carried out following the general procedure described in the notes.6
All products were fully characterized by spectroscopic methods.
Isolated yields.
b
c

W. Liu et al. / Tetrahedron Letters 42 (2001) 2439–2441
2441
to neutral and compatible with a variety of acid/base
sensitive substrates.
A. J. Org. Chem. 1997, 62, 9295–9297; (c) Menger, F. M.;
Vitale, A. C. J. Am. Chem. Soc. 1973, 95, 4931–4934; (d)
Openshaw, H. T.; Whittaker, N. J. Chem. Soc. (C) 1969,
89–91.
Acknowledgements
6. General procedure: To the mixture of lactone 4a (1.0
mmol), benzylamine hydrochloride (1.5 mmol), and NaEH
(2.5 mmol) under nitrogen was charged THF (5 mL), then
the reaction mixture was stirred at room temperature for
12 h. After the lactone was consumed, 5 mL of saturated
sodium chloride aqueous solution and 10 mL of ethyl
acetate were added. The two layers were separated, the
aqueous layer was back-extracted with another 10 mL of
ethyl acetate. Combined organic layers were dried
(MgSO4), filtered and concentrated. The residue was sepa-
rated by chromatography (EtOAc/hexane) to afford the
We would like to thank Drs. Kapa Prasad and Liladhar
Waykole for helpful discussions.
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1
product 4b: mp 167–169°C; [h]2D5 +25.2 (c 1.3, MeOH); H
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