LiNTf2-catalyzed aminolysis of lactones with stoichiometric quantities of amines

Article abstract of DOI:10.1055/s-2007-1000882

LiNTf₂ in the reaction of lactones with amines is able to activate cyclic esters towards ring opening, thus leading to clean open-chain amides under mild conditions and using a stoichiometric amount of amine. The generality of the method was demonstrated by a range of selected lactones and amines. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-1000882

LETTER
189
LiNTf2-Catalyzed Aminolysis of Lactones with Stoichiometric Quantities of
Amines
L
iNTf -Catalyzed
l
A
min
a
olysis of La
u
ctones dia Lalli, Andrea Trabocchi, Gloria Menchi, Antonio Guarna*
2
Dipartimento di Chimica Organica ‘Ugo Schiff’ and Laboratorio per la Progettazione, Sintesi e Studio di Eterocicli Bioattivi
(HeteroBioLab), Università degli Studi di Firenze, Polo Scientifico e Tecnologico,
Via della Lastruccia 13, 50019 Sesto Fiorentino (FI), Italy
Fax +39(055)4573569; E-mail: antonio.guarna@unifi.it
Received 18 September 2007
we were interested in finding an easy and efficient method
Abstract: LiNTf2 in the reaction of lactones with amines is able to
for synthesizing molecules through the aminolysis of lac-
activate cyclic esters towards ring opening, thus leading to clean
tones,8 and in particular we were interested in achieving
open-chain amides under mild conditions and using a stoichiomet-
the reaction using stoichiometric quantities of the reac-
tants. After the initial observation that the addition of sub-
stoichiometric quantities of LiNTF2 could catalyze the
aminolysis of g-butyrolactone (1), we started investigat-
ing the best conditions to achieve optimal conversion us-
ing allylamine (Figure 1), specifically by tuning the
solvent and the temperature, and monitoring the reaction
time until completion.
ric amount of amine. The generality of the method was demonstrat-
ed by a range of selected lactones and amines.
Key words: amides, ring opening, Lewis acids, lactones, catalysis
Lactone aminolysis is a common transformation which al-
lows direct conversion into the corresponding amides, and
it is a highly attractive transformation in modern organic
synthesis, although it generally requires harsh conditions,1
which are limiting factors especially in scale-up proce-
dures. Moreover, excess of amine is generally used to
guarantee proper conversion and reaction rate, making the
direct aminolysis not feasible especially when the amines
are not readily available.2 Several methods have been re-
ported in the literature for facilitating the reaction of lac-
tones with amines,3 and the use of the Weinreb reagents
coming from the reaction of trimethylaluminium with an
amine, or the use of 2-hydroxypyridine have been consid-
ered as being the most popular.4 Recently, Shimizu et al.
reported on the use of Me2AlCl–HN(OMe)Me as an effi-
cient amidating agent.5
Figure 1
Among the three main solvent systems tested, namely
THF, EtOH, and chloroform, the corresponding control
experiments were also carried out at refluxing tempera-
tures, to have reference data on the yields in the absence
of LiNTF2 (Table 1, entries 1–4). Reactions conducted in
EtOH at 95 °C in a sealed vial showed 43% and 62%
yields after 17 hours and 40 hours, respectively (Table 1),
whereas THF and chloroform produced the title amido al-
cohol in 37% and 52% yields, respectively. Addition of
LiNTF2 in THF did not lead to any improvement (entry 5),
as the reaction outcome dropped to 12%, indicating that
this solvent was not compatible with the lithium salt cata-
lyzed aminolysis. The reaction in EtOH and in the pres-
ence of LiNTF2 indicated a small effect of the catalyst, as
a similar yield as the control experiment was achieved at
lower temperature (Table 1, entry 6 vs. entry 2). We next
turned our attention to halogenated solvents, as these were
reported being the systems of choice in the aminolysis of
epoxides,6 probably due to their low coordinating effect
towards the catalyst, thus resulting in a lower interference
in the process. Dichloromethane was tested at different
temperatures, giving at 40 °C yields similar to EtOH, with
no additional improvement observed on prolonging the
reaction time from 17 hours to 72 hours (entries 7–9). Al-
so, the addition of 10% 1,1,1,3,3,3-hexafluoroisopropanol
(HFIP) produced the same result as that in pure dichlo-
romethane, indicating no beneficial effect to the reaction
As lactone aminolysis is commonly carried out in multi-
step synthesis, there is an interest for versatile activators
which could be of great benefit, especially where stoichio-
metric amounts of valuable building blocks have to be
used. Recently, Cossy et al. reported the application of
LiNTf2 as an efficient activator towards regioselective
ring opening of epoxides with a variety of nucleophiles in-
cluding amines.6 This process was adopted by our group
as a tool to synthesize intermediate compounds on the
gram scale.7 We reasoned that a similar effect could exist
with respect to oxygen atoms of lactones, as a conse-
quence of activation of the carbonyl group towards nu-
cleophilic aminolysis, thus opening the route towards a
general and facile method for the ring opening of lactones
of different ring size with amines belonging to different
classes. Specifically, as a part of a program towards the
development of heterocycles carrying chemical diversity,
SYNLETT 2008, No. 2, pp 0189–0192
x
x.
x
x.
2
0
0
7
Advanced online publication: 21.12.2007
DOI: 10.1055/s-2007-1000882; Art ID: D29407ST
© Georg Thieme Verlag Stuttgart · New York

190
C. Lalli et al.
LETTER
(entry 10). These preliminary experiments suggested that We next investigated the generality of the process by per-
the solvent plays a role in the reaction, and that an aprotic forming the reaction with lactones varying in ring size and
solvent with a high polar character might allow the lithi- in substitution pattern, and also using amines of different
um salt to work optimally in activating the carbonyl group steric and nucleophilic characters. Ring opening of g-bu-
towards the ring-opening aminolysis. In fact, chloroform tyrolactones was explored with secondary amines, and
showed a marked improvement with respect to dichlo- while piperidine gave quantitative yield, the bulky diiso-
romethane when the reaction was carried out at reflux propylamine did not yield any product, suggesting the rel-
temperature and the yield was raised to 83% (entry 12). evance of steric hindrance (Table 2, entries 2 and 3). Also,
Finally, the best conditions were achieved by prolonged the nucleophilic character of the amine influenced the re-
reaction of g-butyrolactone and allylamine in stoichiomet- action conversion, as benzylamine and butylamine gave
ric amounts, in chloroform at 85 °C for 40 hours, giving a 100% yield, whereas aromatic p-anisidine gave the adduct
clean product in quantitative yield (entry 13).9 Further at- in only 11% yield and the corresponding lactam resulting
tempts to lower both the temperature and the catalyst load from subsequent cyclization of the hydroxyamide in 12%
resulted in lower yield (entries 14–16). Whenever an in- yield (entry 6).
complete reaction was observed, the crude mixture con-
Surveying the ring size of lactones indicated that the reac-
tained only the starting material and the title product,
tions of 4–6-membered rings proceeded in almost quanti-
without significant amount of degraded material.
tative yields, and that e-caprolactone reacted under these
conditions to furnish the corresponding product in 53%
yield (Table 2, entries 7–9). The presence of unprotected
functional groups, and in particular of hydroxyl functions,
Table 1 Aminolysis of g-Butyrolactone with Allylamine (1 equiv)
in a Sealed Vial
Entry Solvent
Temp
(°C)
Reaction LiNTf2 Yield
time (h) (equiv) (%)
proved to influence negatively the outcome of the reaction
(entries 12 and 13), probably by interfering with the lithi-
um salt. In particular, unprotected erythronolactone 20
failed to react, giving the adduct in only 6% yield, where-
as the corresponding isopropylidene derivative 22, having
the two hydroxyls embedded in the dioxolane ring, react-
ed cleanly to produce the adduct in 93% yield (entries 13
and 14, respectively). Similarly, a-benzyloxy-g-butyro-
lactone (24) reacted quantitatively, compared to the corre-
sponding unprotected a-hydroxy-g-butyrolactone (18),
which furnished the amido alcohol in 46% yield (entries
15 and 12, respectively), thus corroborating the impor-
tance of having protic functional groups protected. In all
cases, the amides resulting from aminolysis of the corre-
sponding lactones were easily purified by standard flash
chromatography.
1
2
THF
85a
95a
95a
85a
50
24
17
40
40
17
17
17
17
72
17
17
17
40
17
40
40
0
37
43
62
52
12
62
33
58
60
38
48
83
99
43
62
60
EtOH
0
3
EtOH
0
4
CHCl3
0
5
THF
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.2
0.1
6
EtOH
50
7
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2–HFIP (9:1)
ClCH2CH2Cl
CHCl3
20
8
40
9
40
10
11
12
13
14
15
16
20
Finally, preliminary investigations indicated that this cat-
alytic system worked with even more unactivated carbox-
ylic esters, as the amidation of Boc-Ala-OMe with
allylamine in the presence of 0.5 equivalent of LiNTf2 un-
der standard conditions furnished the corresponding Boc-
alanine allylamide in 52% yield, whereas only the starting
reagents were obtained in the corresponding control ex-
periment without the lithium salt. Similar results were ob-
tained for the synthesis of protected hydroxamic acids
from lactones, as the reaction of g-butyrolactone with O-
benzylhydroxylamine resulted in 45% yield under stan-
dard conditions compared to 0% yield in the control ex-
periment, thus indicating the possibility of preparing N-
hydroxamic acids from lactones by this method.
20
85a
85a
20
CHCl3
CHCl3
CHCl3
85a
85a
CHCl3
a Oil-bath temperature corresponding to reflux condition in the sealed
vial.
As a hypothesized mechanism relating to the activating
role of LiNTf2 towards lactone aminolysis, the coordinat-
ing effect of the lactone carbonyl group was considered.
Thus, the interaction of the strong electron-withdrawing
lithium salt with the C=O bond would increase the elec-
trophilic character of the carbonyl carbon atom towards
nucleophilic addition of the amine, thus resulting in high-
er yield of the corresponding hydroxyamide.
In conclusion, we have reported a mild and effective
method for the aminolysis of lactones with stoichiometric
quantities of amines, which consists of the use of LiNTf2
as an activator of the carbonyl function of the lactone. The
method was developed using chloroform as solvent, and
the generality of the reaction was demonstrated with se-
lected amines and lactones, indicating the importance of
avoiding steric hindrance and of the protection of protic
Synlett 2008, No. 2, 189–192 © Thieme Stuttgart · New York

LETTER
LiNTf2-Catalyzed Aminolysis of Lactones
191
Table 2 Reaction f Various Lactones with Amines
Entry Amine
Lactone
Product
Yield Entry Amine Lactone
(%)
Product
Yield
(%)
O
OH
H
N
O
O
H
O
allylamine
(2)
N
HO
1
2
99
9
2
2
53
80
O
O
O
1
3
12
14
13
H
N
N
O
piperidine
1
1
100 10
O
HO
HO
O
O
4
15
HO
H
N
diisopropy-
lamine
O
O
3
–
0
11
2
64
16
18
17
OH
O
O
H
N
H
N
4
5
benzylamine 1
100 12
2
2
46
6
HO
HO
OH
O
O
O
19
5
HO
OH
OH
H
N
H
N
HO
butylamine
1
1
99 13
HO
O
O
OH
O
6
20
21
O
O
O
OH
O
O
H
p-methoxy-
11a 14
2
93
N
6
benzylamine
NH
HO
O
O
O
O
7
22
23
O
O
H
O
O
HO
N
H
O
7
8
2
2
100 15
2
2
99
80
N
O
HO
O
8
O
9
24
25
27
OH
O
O
O
H
MeOOC
O
N
5
16
O
26
10
11
a The corresponding butyrolactam was also obtained in 12% yield.
functional groups for optimal conversions. The method
was also tested for the reaction of allylamine with the
methyl ester of Boc-alanine, and for the lactone aminoly-
sis of g-butyrolactone with protected hydroxylamine, in-
dicating the possibility of a more general application of
LiNTf2-catalyzed reactions of lactones and esters.
Acknowledgment
The University of Florence and MUR are acknowledged for finan-
cial support. The authors thank Ms Brunella Innocenti for technical
support.
References and Notes
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Synlett 2008, No. 2, 189–192 © Thieme Stuttgart · New York

192
C. Lalli et al.
LETTER
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(8) Unpublished data.
(9) General Procedure for Lactone Aminolysis; Synthesis of
N-Allyl-4-hydroxybutyramide(3): To a solution of g-
butyrolactone (1; 1 equiv) and allylamine (2; 1 equiv) in
anhyd CHCl3 (0.5 mL/mmol) was added under a nitrogen
atmosphere LiNTf2 (0.5 equiv). The mixture was stirred in a
sealed vial at 85 °C (oil bath) for 40 h, then it was washed
with a sat. NaHCO3 solution, and the organic phase was
evaporated to give the title product as a clean viscous oil
(99%). 1H NMR (200 MHz, CDCl3): d = 6.62 (br, 1 H, NH),
5.73–6.03 (m, 1 H, =CH), 5.04–5.23 (m, 2 H, =CH2), 4.02
(br, 1 H, OH), 3.88 (t, J = 5.5 Hz, 2 H), 3.72 (t, J = 5.5 Hz, 2
H), 2.40 (t, J = 6.2 Hz, 2 H), 1.79–1.96 (m, 2 H). 13C NMR
(50 MHz, CDCl3): d = 178.2 (s, C=O), 137.1 (d, =CH), 119.4
(t, =CH2), 65.1 (t, CH2), 45.4 (t, CH2), 36.4 (t, CH2), 31.5 (t,
CH2). MS (EI, 70 eV): m/z (%) = 143 (1) [M+], 99 (28), 84
(10), 69 (14), 57 (100). Anal. Calcd for C7H13NO2: C, 58.72;
H, 9.15; N, 9.78. Found: C, 58.70; H, 9.14; N, 9.76.
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Synlett 2008, No. 2, 189–192 © Thieme Stuttgart · New York

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