Methylaluminoxane (MAO)-assisted direct amidation of esters

Article abstract of DOI:10.1055/s-0034-1378927

Aliphatic and aromatic esters are efficiently transformed into amides in good to excellent yields, under mild conditions using methylaluminoxane (MAO). This reaction can be performed either at room temperature or by applying microwave irradiation.

Full text of DOI:10.1055/s-0034-1378927

SYNLETT
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© Georg Thieme Verlag Stuttgart · New York
2015, 26, 385–387
letter
385
S. Desrat et al.
Letter
Synlett
Methylaluminoxane (MAO)-Assisted Direct Amidation of Esters
Sandy Desrat
[-Al(Me)-O-]5–20 (MAO)
O
O
R4
Aline Ducousso
Shelly Gapil
+
HN
R3
R1
OR2
R1
NR3R4
r.t., 5 h or MW, 110 °C, 15 min
Camille Remeur
Fanny Roussi*
Institut de Chimie des Substances Naturelles, CNRS UPR 2301,
1 Avenue de la Terrasse, 91198 Gif-sur-Yvette Cedex, France
+
3
3
1
(6
)
9
0
7
7
2
4
7
fanny.roussi@cnrs.fr
Received: 15.09.2014
Accepted after revision: 13.10.2014
Published online: 27.11.2014
laboratory is more limited, although Lipshutz recommend-
ed using it as a cocatalyst to improve the efficiency of car-
boalumination reactions.5
DOI: 10.1055/s-0034-1378927; Art ID: st-2014-d0766-l
In order to validate the use of MAO as a safe substitute
for trimethylaluminium, we studied the direct amidation of
methyl cinnamate (1) with butylamine (2a). As expected,
stirring compounds 1 and 2a at room temperature for 18
hours only resulted in recovery of starting materials (Table
1, entry 1), while addition of MAO (10% in toluene) led to
the formation of the desired amide 2. The conversion rate
was proportional to the amount of MAO added (from 0.2–2
equiv, Table 1, entries 2–5). With three equivalents of MAO,
the conversion was almost complete in five hours (Table 1,
entries 6 and 7). To reduce the amount of amine while
keeping a good conversion rate, the reaction was performed
at higher temperatures (Table 1, entries 8 and 9). Despite
the stability of MAO under these conditions and the im-
provement of the conversion rate (Table 1, entries 4 and 8),
the reaction was not complete. As we noticed an increase in
the rate and speed of the conversion at higher tempera-
tures, the reaction was carried out at 110 °C under micro-
wave irradiation. Using three equivalents of MAO and two
equivalents of n-butylamine, conversion was complete in a
few minutes (Table 1, entries 11–14), whereas only the
starting ester was recovered after 15 minutes when MAO
was not used (Table 1, entry 10). Moreover, the reaction is
chemoselective since the 1,4-addition product was never
observed in the crude mixture. Finally, mixing the ester
with two equivalents of amine, three equivalents of MAO
either at room temperature for five hours or at 110 °C for 15
minutes under microwave irradiation gave the best results.
The scope of this MAO-mediated direct amidation of es-
ter was then studied by varying the amines 2a–14a. The re-
sults of both method A (room temperature) and method B
(microwave heating at 110 °C for 15 min) are detailed in Ta-
ble 2.6 Regardless of the conditions used, a complete con-
version of ester 1 into the corresponding amide was
observed for the less-hindered amines such as aniline (3a),
benzylamine (4a), N-methylbenzylamine (5a), pyrrolidine
(6a), morpholine (7a), n-butylamine (2a), and isopropyl-
amine (8a; Table 2, entries 1–7). Despite these excellent
conversions, the amide derived from pyrrolidine 6a was ob-
Abstract Aliphatic and aromatic esters are efficiently transformed into
amides in good to excellent yields, under mild conditions using methyl-
aluminoxane (MAO). This reaction can be performed either at room
temperature or by applying microwave irradiation.
Key words amidation, MAO, esters, amides, microwave
Amide-bond formation is a fundamental reaction in or-
ganic chemistry considering the frequent occurrence of
amides in natural and pharmaceutical compounds.1 Devel-
opment of new and direct methods of amide synthesis is of
great interest as existing ones may present some limita-
tions due to the use of expensive reagents or the applica-
tion of harsh conditions. Thus, in recent years, various
complementary methods of direct amidation of esters or
acids have been published in the literature.2
Aluminium-mediated amine activation, developed by
Weinreb in the late 1970s,3a is one of the most general
methods for direct amide-bond formation. A safer high-
throughput version of this reaction has recently been devel-
oped using a microreactor system,3b and the scope of the
reaction was extended to carboxylic acids.3c However,
trimethylaluminium is highly pyrophoric and thus danger-
ous to handle on a large scale. In addition, the aluminium-
amide intermediate is unstable at high temperatures and
may lead to exothermic reaction even at room temperature.
All these drawbacks have made this reaction inappropriate
for many conversions despite its potential versatility.
We report herein the use of methylaluminoxane4 (MAO)
as a safe alternative to trimethylaluminium-mediated am-
ide-bond formation. MAO is prepared by controlled hydro-
lysis of trimethylaluminium. Its structure is schematically
represented as [–Al(Me)O–]5–20 although, despite extensive
research and many attempts to propose structural models,
its exact composition remains unknown.4a Nevertheless,
MAO is a very powerful cocatalyst used in combination
with group 4 metallocenes for the polymerization of α-ole-
fins on an industrial scale. However, its application in the
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 385–387

386
S. Desrat et al.
Letter
Synlett
Table 1 Optimization of the Amidation Reaction Conditions
Table 2 Scope of the Direct Amidation of Methyl Cinnamate (1)
O
O
O
MAO (3 equiv)
O
H2N
HNR1R2 (2 equiv)
2a
NR1R2
OMe
N
H
OMe
MAO
1
2
method A: r.t., 5 h
method B: MW, 110 °C,
15 min
1
2–14
Entry 2a (equiv)
MAO
Temp
Time
Conv. (%)a
(equiv)
Conv.
Yield
Entry
1
Amine
H2N
Method
(%)a
(%)b
1
2
1
1
1
1
1
1
2
1
1
2
2
2
2
2
0
0.2
0.5
1
r.t.
r.t.
18 h
18 h
18 h
18 h
5 h
0
24
40
66
57
94
>95
81
82
0
A
B
>95
>95
3a
4a
85
3
r.t.
4
r.t.
H2N
Me
A
B
>95
>95
5
2
r.t.
2
83
6
3
r.t.
5 h
7
3
r.t.
5 h
N
A
B
>95
>95
3
4
5a
6a
90
43
H
8
1
80 °C
5 h
9
1
110 °C
110 °C (MW)
110 °C (MW)
110 °C (MW)
110 °C (MW)
110 °C (MW)
5 h
HN
HN
A
B
>95
>95
10
11
12
13
14
0
15 min
5 min
3
85
>95
>95
>95
A
B
>95
>95
3
10 min
15 min
30 min
5
6
7
7a
2a
8a
73
97
99
O
3
A
B
>95
>95
3
H2N
a Conversion of 1 into 2 calculated from 1H NMR spectrum of the crude mix-
ture.
A
B
>95
>95
H2N
H2N
A
B
52
43
8
9
9a
40
60
tained with only a moderate yield (Table 2, entry 4) due to
difficulties in extraction. Furthermore, bulkier amines like
tert-butylamine (9a), diethylamine (10a), and diisopropyl-
amine (11a, Table 2, entries 8–10) led to the corresponding
amides with lower yields due to incomplete conversion
(close to zero for 11a). The Weinreb amide 12 (Table 2, en-
try 11) could be obtained with a satisfactory yield but only
at room temperature. Indeed, degradation was observed
under microwave irradiation in the presence of N,O-di-
methylhydroxylamine (12a). Hydrazines could also be used
as substrates for direct amidation. The phenylhydrazine
(13a) gave the expected N-phenylhydrazide (13) with a rea-
sonable yield after purification (Table 2, entry 12) whereas
the methylhydrazide (Table 2, entry 13) could not be isolat-
ed. Indeed an intramolecular Michael addition occurred
leading to 5-phenylpyrazolidine-3-one in this case. The low
yield observed in the amidation of the 1,1-dimethylhydra-
zine (Table 2, entry 14) suggests that the secondary amine
of the hydrazines is more reactive than the terminal prima-
ry ones, thus leading to the branched N-substituted hydra-
zides.
A
B
71
61
N
10a
H
A
B
14
0
9
–
10
11
11a
12a
N
H
Me
O
A
B
60
0
55
–
N
Me
H
H
N
A
B
>95
>95
45c
H2N
12
13a
H
N
A
B
>95
>95
13
14
14a
15a
42c,d
<10c
H2N
H2N
Me
Me
N
A
B
12
17
Me
a Conversion of 1 into amide calculated from 1H NMR spectrum of the
crude mixture.
b Average yield obtained after aqueous HCl washing.
c Average yield obtained after flash chromatography on silica gel.
d The pyrazolidine-3-one was obtained.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 385–387

387
S. Desrat et al.
Letter
Synlett
Finally, the impact of the nature of the ester was studied
(Table 3). For this purpose, benzylamine (4a) was stirred
with different esters and MAO for 15 minutes with micro-
wave heating. The reaction was found to be sensitive to the
steric bulk of the aliphatic leaving groups. Indeed, a de-
crease in the conversion rate of the ester into the amide was
observed between the methyl, isopropyl, and tert-butyl
group (Table 3, entries 1–3). The phenyl and benzyl esters
19 and 20 led to the corresponding amide with very good
yields (Table 3, entries 4 and 5). Moreover, despite the lower
conversion rate, the aliphatic amide resulting from methyl
butyrate 21 could be obtained in a moderate yield (Table 3,
entry 6). This can probably be explained by ester volatility.
Carboxylic acids were also tested under the same condi-
tions but did not give the expected amides.
In conclusion, a new and efficient method for the direct
amidation of esters is disclosed using MAO as a safe alterna-
tive to trimethylaluminium. This easy-to-handle reaction
can be performed either at room temperature or within a
few minutes on exposure to microwave irradiation. More-
over, the conditions are well tolerated by a great range of
amines and esters, despite the unfavorable influence of ste-
ric bulk of the reactants; although, this feature could be ap-
plied to develop selective amidation reactions in the
presence of different esters.
Acknowledgment
The authors are grateful for the funding provided by the ANR
(ANR2010-JCJC-702-1) as well as for a grant from the University of
Malaya and the French embassy in Malaysia (S.G).
Table 3 Influence of the Nature of Ester in Direct Amidation
References and Notes
O
ester (1 equiv), MAO (3 equiv)
NH2
(1) (a) Valeur, E.; Bradley, M. Chem. Soc. Rev. 2009, 38, 606.
(b) Pattabiraman, V. R.; Bode, J. W. Nature (London, U.K.) 2011,
480, 471.
R
N
MW, 110 °C, 15 min
H
4a
(2) (a) Gooβen, L. J.; Ohlmann, D. M.; Lange, P. P. Synthesis 2009,
160. (b) Veitch, G. E.; Bridgwood, K. L.; Ley, S. V. Org. Lett. 2008,
10, 3623. (c) Kim, B. R.; Lee, H.-G.; Kang, S.-B.; Sung, G. H.; Kim,
J.-J.; Park, J. K.; Lee, S.-G.; Yoon, Y.-J. Synthesis 2012, 44, 42.
(d) Huang, Z.; Reilly, J. E.; Buckle, R. N. Synlett 2007, 1026. (e) Al-
Zoubi, R. M.; Marion, O.; Hall, D. G. Angew. Chem. Int. Ed. 2008,
2876. (f) Gernigon, N.; Al-Zoubi, R. M.; Hall, D. G. J. Org. Chem.
2012, 77, 8386. (g) Bao, Y.-S.; Zhaorigetu, B.; Angula, B.; Baiyin,
M.; Jia, M. J. Org. Chem. 2014, 79, 803. (h) Han, C.; Lee, J. P.;
Lobkovsky, E.; Porco, J. A. J. Am. Chem. Soc. 2005, 127, 10039.
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Chem. 2011, 76, 2853.
(3) (a) Basha, A.; Lipton, M.; Weinreb, S. M. Tetrahedron Lett. 1977,
48, 4171. (b) Gustafsson, T.; Ponten, F.; Seeberger, P. H. Chem.
Commun. 2008, 1100. (c) Chung, S. W.; Uccello, D. P.; Choi, H.;
Montgomery, J. I.; Chen, J. Synlett 2011, 2072.
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Entry
1
Ester
Conv. (%)a
Yield (%)b
O
O
O
O
O
O
>95
90
90
OMe
Oi-Pr
Ot-Bu
OPh
16
17
18
19
2
3
4
5
6
75
50
38
87
88
54
>95
>95
80
(5) Lipshutz, B. H.; Butler, T.; Lower, A. J. Am. Chem. Soc. 2006, 128,
15396.
(6) General Procedures
Method A: To a mixture of ester (1 mmol) and amine (2 mmol)
under an argon atmosphere was added a 10% solution of MAO
in toluene (2 mL, 3 mmol). After 5 h at r.t., the solution was
diluted with MTBE (3 mL) and quenched by addition of 10% aq
NaOH (2 mL). The product was then extracted with MTBE (3×)
and the combined organic layers were washed with a 1 M solu-
tion of HCl, dried over MgSO4, filtered, and concentrated under
reduced pressure to give usually the pure product (purity >90%).
Less pure products were purified by flash chromatography on
silica gel using a mixture of heptane and EtOAc.
OBn
20
21
OMe
Method B: A mixture of ester (1 mmol) and amine (2 mmol)
was placed in a MW vial under an argon atmosphere. A 10%
solution of MAO in toluene (2 mL, 3 mmol) was then added, and
the mixture was irradiated and stirred for 15 min at 110 °C. The
solution was then cooled to r.t. and diluted with MTBE. The
products were isolated in the same manner as in method A.
a Conversion of ester into amide calculated from 1H NMR spectrum of the
crude mixture.
b Yield of isolated product obtained after flash column chromatography on
silica gel.
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