Amide bond formation using an air-stable source of AlMe3

Article abstract of DOI:10.1016/j.tetlet.2006.06.004

Synthesis of amides from coupling esters with a range of primary amines can be conveniently achieved in moderate to excellent yields (69-99%) using an air-stable adduct of trimethylaluminium (AlMe₃)₂·DABCO (DABCO is 1,4-diazobicyclo[2.2.2]octane), referred to as DABAL-Me₃. Reactions can be run without requiring the exclusion of atmospheric oxygen or the drying of solvents.

Full text of DOI:10.1016/j.tetlet.2006.06.004

Tetrahedron Letters 47 (2006) 5767–5769
Amide bond formation using an air-stable source of AlMe3
Andrew Novak,a Luke D. Humphreys,b Matthew D. Walkerb and Simon Woodwarda,*
aSchool of Chemistry, The University of Nottingham, Nottingham NG7 2RD, United Kingdom
bGlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage SG1 2NY, United Kingdom
Received 31 March 2006; revised 23 May 2006; accepted 1 June 2006
Available online 21 June 2006
Abstract—Synthesis of amides from coupling esters with a range of primary amines can be conveniently achieved in moderate to
excellent yields (69–99%) using an air-stable adduct of trimethylaluminium (AlMe3)2ÆDABCO (DABCO is 1,4-diazobicyclo-
[2.2.2]octane), referred to as DABAL–Me3. Reactions can be run without requiring the exclusion of atmospheric oxygen or the
drying of solvents.
ꢀ 2006 Elsevier Ltd. All rights reserved.
Direct formation of amides from the corresponding
unactivated esters and lactones is a desirable synthetic
operation as hydrolysis to the parent carboxylic acid
and its subsequent activation is avoided.1–3 Amine acti-
vation is most easily achieved by the formation of an
aluminium amide4 (R2AlNR2) from exposure of amines
or their HCl salts to AlMe3,5 or DIBAL–H.6 Subse-
quent ester aminolysis delivers the desired amides in
excellent yields. The power of this methodology is illus-
trated by its application to numerous modern syntheses
of complex organic molecules.7 A major drawback to
this chemistry is the pyrophoric nature of the aluminium
reagents used and the subsequent need for strict exclu-
sion of air and moisture. Recently, we demonstrated
that the remarkably air-stable AlMe3 adduct (AlMe3)2Æ
DABCO (DABCO = 1,4-diazobicyclo[2.2.2]octane) 1,
which we call DABAL–Me3,8 could be formed in one
step from DABCO and AlMe3, and although somewhat
moisture sensitive this can be easily handled without the
need for an inert atmosphere.9 We were pleased to ob-
serve that while DABAL–Me3 1 is an extremely conve-
nient source of methyl carbanions,9–11 it retains
sufficient Lewis acidity to render it capable of amine
activation.
conversion of the ester to N-benzylbenzamide.12 In com-
parison to the aminolysis of esters with Me2Al–HNR
that are commonly run at ambient temperature in
CH2Cl2,5 reactions utilizing the air-stable DABAL–
Me3 1 reagent favour THF as solvent. Use of THF
allows complete solubility of reagent 1 and enables the
use of elevated temperatures to promote complete con-
version of the reaction (Scheme 1). In the absence of
the DABAL–Me3 reagent 1 no coupling was observed.
Application of this methodology to the aminolysis of a
range of amines revealed excellent generality with benz-
ylic, aromatic and aliphatic primary amines exhibiting
good reactivity (Table 1).13 A variety of simple esters
participated well in the reaction including b-keto and
a-hydroxy esters. Previously we have found that expo-
sure of DABAL–Me3 1 to substrates possessing enoliz-
able protons led to undesirable side reactions.9–11
Interestingly, the use of a b-keto ester gave the desired
amides in good yield (entries 5 and 9). We postulate
that formation of the enolate, due to the presence of
AlMe3
i) THF, N2, 40 oC, 1 h
O
N
R1NH2
A brief optimization study on the aminolysis of ethyl
benzoate with benzylamine revealed that using 1.5 equiv
of both amine and DABAL–Me3 1 gave a quantitative
R1
N
R2
ii)
O
N
H
R2
OR3
AlMe3
DABAL-Me3
1
THF, N2, reflux, 18 h
iii) 2 M HCl
*
Corresponding author. Tel.: +44 115 9513541; fax: +44 115
9513564; e-mail: Simon.Woodward@nottingham.ac.uk
Scheme 1. Aminolysis of esters using DABAL–Me3 1.
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.06.004

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A. Novak et al. / Tetrahedron Letters 47 (2006) 5767–5769
Table 1. Synthesis of amides using DABAL–Me3 1a
Entry
1
Amine
Ester
Amide
Ph
Yieldb (%)
99 (99c)
O
O
O
O
Ph
NH2
N
H
Ph
EtO
Ph
O
2
3
69 (70c)
88
Ph
Ph
NH2
NH2
Ph
N
H
n-BuO
O
Ph
Ph
Ph
N
H
EtO
O
O
4
99
OH
O
OH
O
Ph
Ph
NH2
NH2
EtO
Ph
N
H
O
O
O
5
6
90
98
Ph
Ph
N
H
MeO
MeO
O
N
H
Ph
Ph
NH2
Ph
O
O
7
8
PhNH2
91
Ph
N
Ph
EtO
Ph
H
O
O
O
O
O
n-BuNH2
99 (99c)
n
-Bu
-Bu
N
Ph
MeO
Ph
H
O
O
O
9
10
11
n-BuNH2
t-BuNH2
89
97
86
n
N
H
MeO
MeO
MeO
O
t-Bu
N
Ph
Ph
Ph
H
O
NH2
N
Ph
H
a Reactions performed on a 0.50 mmol scale using amine (1.5 equiv), DABAL–Me3 1 (1.5 equiv), anhydrous THF, N2, 40 ꢂC, 1 h followed by ester
(1 equiv), reflux, 18 h.
b Isolated products.
c Reactions performed on a 0.50 mmol scale using amine (1.5 equiv), DABAL–Me3 1 (1.5 equiv), undried THF, open to air, 40 ꢂC, 1 h followed by
ester (1 equiv), reflux, 18 h.
DABCO, acts by deactivating the more reactive car-
bonyl group allowing aminolysis to occur smoothly.
Unfortunately, the presence of an aldehyde functionality
was not tolerated. The use of c-formyl esters resulted in
the formation of several unidentified products while
methyl 4-formyl benzoate was recovered quantitatively,
presumably through C@N formation via preferential
attack of aluminium amide at the more reactive
carbonyl centre and subsequent hydrolysis of the imine
back to aldehyde upon aqueous workup.
amide bond formation.15 Additionally, it is particularly
suited to the preparation of small scale amide libraries.
In summary we have developed a convenient and highly
practical method for the direct aminolysis of esters with
aluminium amides, utilizing an air-stable form of
AlMe3. The reactions require no precautions to exclude
air or moisture and in all cases the reactions result in full
conversion of the starting esters with analytically pure
amides being attained without the need for further
purification.
In attempts to further simplify the experimental proce-
dure we were pleased to discover that the reaction can
be performed without adhering to a strictly anhydrous
protocol. Simply running reactions in commercial un-
dried THF and open to the atmosphere made little to
no difference in the yield of amide attained.14 Our
method is complimentary to the recent approaches to
Acknowledgements
Financial support from the EU associated with the Lig-
Bankꢁ project (FP6-NMP3-CT-2003-505267) and the
COST D-24 program is acknowledged. One of us is

A. Novak et al. / Tetrahedron Letters 47 (2006) 5767–5769
5769
10. Biswas, K.; Chapron, A.; Cooper, T.; Fraser, P. K.;
Novak, A.; Prieto, O.; Woodward, S. Pure Appl. Chem.
2006, 78, 511–518.
grateful to GlaxoSmithKline for the provision of a
studentship (A.N.).
11. Cooper, T.; Novak, A.; Humphreys, L. D.; Walker, M.
D.; Woodward, S. Adv. Synth. Catal. 2006, 348, 691–
695.
References and notes
12. Reactions to form secondary amides, including Weinreb
amides, do not give acceptable yields under the present
procedure.
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DABAL–Me3 1 (194 mg, 0.75 mmol) in anhydrous THF
(4 mL) under an inert atmosphere, benzylamine (82 lL,
0.75 mmol) was added. The solution was stirred and
warmed to 40 ꢂC for 1 h. To this ethyl benzoate (62 lL,
0.50 mmol) was added and the solution was refluxed for
18 h. The reaction mixture was cooled to ambient
temperature and quenched with aqueous HCl (2 M,
5 mL) dropwise, followed by extraction with diethyl ether
(2 · 10 mL). The organic phase was separated and filtered
through a small plug of silica. Removal of the solvent
under reduced pressure gave N-benzylbenzamide (105 mg,
99%) as a colourless powder. Use of lower stoichiometries
of DABAL–Me3 (e.g., Table 1, entry 1, but 1.0 equiv) led
to a reduction in the yield of amide to 70%. Below
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unacceptable.
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14. Reaction performed as in the general procedure using
standard undried glassware and all stages carried out in
air. Lower specification grades of THF (containing up to
0.05% w/w water) were used directly from the bottle as
supplied without the need for pre-drying.
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