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Table 1
explored the reactivity of different amino acids by varying N-termi-
nus protection.
Time required for completion is independent of N-protection
For our ongoing research, we needed benzyl amides of various
amino acid derivatives. Among many protocols available in litera-
ture we chose the one reported by Perreux et al.26 as they avoided
the use of –COOH activating reagent, catalyst or extra solvent. We
first tried to reproduce the original work using benzyl amine and
phenyl acetic acid in a domestic microwave oven at 160 °C (con-
vection heating mode) instead of a dedicated microwave reactor
(SynthwaveÒ 402 from Prolabo was used in the original article)
and found the amide was produced in good yield. However, replac-
ing phenyl acetic acid with benzoyl glycine produced only a trace
amount of amide.
The relative inertness of carboxylic acid group of amino acids to-
wards amidation prompted us to follow mild activation strategy by
forming benzyl ester. Benzyl group is commonly used for C-protec-
tion of amino acids similar to methyl and ethyl esters. When benzyl
ester of N-benzoyl glycine was reacted with 10 equiv of benzyl
amine for 30 min at 160 °C under a microwave heating it gave cor-
responding amide in good yield. Thus the use of benzyl ester is
more efficient and convenient compared to the methods using
unprotected amino acids. This result inspired us to explore the pos-
sibility of preparation of amides from inactive esters of amino acids.
At first, various parameters were optimized to find out the best con-
dition for such reactions. There was no decrement in the yield of the
product with decrease in the temperature of the microwave oven
(reactions were performed at 160, 120, 100 and 40 °C). Later we re-
peated the reaction in a shaking incubator at 40 °C (Scheme 1).
Since incubator provides uniform heating we considered it as a bet-
ter option. If desired, an oil bath or a microwave oven also can be
used. Subsequently, from several trials we found that the use of
3 equiv of amine was found to be equally effective in giving corre-
sponding amide.
After completion of the reaction (monitored by TLC), the reac-
tion mixture was directly loaded on to a silica gel column. Our de-
sired amide along with benzyl alcohol, which was produced during
the course of the reaction and unreacted amine, was separated and
collected back easily.
Other common N-protecting groups such as Boc and Cbz were
found to be compatible under the present experimental condi-
tion27 as shown in Table 1.
Next, we investigated the reactivity of esters of neutral amino
acids such as, Ala, Leu, Val and Phe as shown in Table 2. It was ob-
served that the time required for complete conversion is very much
dependent on the side chain present. With the increase in the bulk-
iness of the group at the side chain time required for complete
conversion is more. Also it was noticed that in the case of Boc valine
benzyl ester (entry 4, Table 2) the reaction mixture was solidified
after 36 h and TLC analysis indicated the partial conversion with
only 40% yield. Addition of more amine and increase in temperature
did not improve further yield. However, phenylalanine derivatives
gave excellent yield (85%) within 25 h for the complete conversion
(entry 5, Table 2). This method was also equally successful for Leu
derivative (entry 3, Table 2) and no precipitation was observed as
in the case of Val derivative in spite of similar bulkiness in their side
chain.
Entry
Benzyl ester
Amine
Time (h)
1
2
3
Bz-Gly-OBn
Boc-Gly-OBn
Cbz-Gly-OBn
BnNH2
BnNH2
BnNH2
2.5
2.5
2.5
amidation condition to several amino acid benzyl esters with var-
ious aliphatic primary and secondary amines as well as aromatic
primary amines (Table 3). Various aliphatic primary amines such
as, n-butylamine, benzylamine, cyclohexylamine and 2-picolyl-
amine react efficiently giving corresponding amides as shown in
Table 3. In the case of ethanolamine, a bis-nucleophile, regioselec-
tive amidation occurs over transesterification. (entry 1, Table 3) In
case of alanine derivatives the time required for complete amida-
tion for ethanolamine was about 1 h (entry 11) which probably
was because of the presence of a more bulky methyl group. Pri-
mary aromatic amines such as aniline did not react with benzyl es-
ter of benzyl amine in the current condition. However, when
heated at 120 °C for 4 h conversion completed was achieved (entry
8) as judged from the TLC.
Further we were interested to explore the feasibility of the cur-
rent methodology for secondary amines as well. When a cyclic sec-
ondary amine, for example, piperidine, was used under the
optimized condition complete conversion was observed within
6 h (entry 10). However, bulky diisopropyl amine did not react
up to 24 h under the present condition (entry 18) when reacted
with uncongested glycine benzyl ester. The same reaction mixture
was heated at 80 °C for further 12 h and no progress was noted and
unreacted starting material was recovered quantitatively. This
could be due to the steric congestion of the isopropyl groups on
the nucleophilic nitrogen atom.
All the final products in the above table were characterized
using NMR, IR and HRMS. Moreover, the structure of the products
of entry 7 and 13 of Table 3 were further confirmed from the X-ray
crystallography. The ORTEP diagrams along with atomic number-
ing of the compounds are furnished below (Fig. 1 and Fig. 2). (Crys-
tallographic data in detail are provided in the Supplementary data.)
We investigated the scope of this methodology with other inac-
tive esters of amino acids that are commonly employed as protect-
ing agents under the same reaction conditions and results are
given in the following table.
We investigated the scope of this methodology under the same
reaction condition with other inactive esters of amino acid that are
commonly employed as protecting groups and results are summa-
rized in Table 4.
It is clear from the data presented in Table 4, that present meth-
odology is applicable to various other inactive esters as well. Reac-
tions with both benzyl and allyl are faster than ethyl and methyl
esters as the first two are better leaving group.
It is noteworthy that, if in any molecule any of these moieties
are employed as protecting group(s) presence of free or bound
amine (as discussed above) in the reaction mixture could generate
amides, if the reaction condition is maintained at or above 40 °C.
This information is particularly important for peptide chemists as
these esters are frequently used as protecting groups for the car-
boxylic acid terminus of an amino acid. Moreover, medicinal chem-
ists may need a library of esters as well as amide derivatives of
amino acids as reported by Geurts et al.2 In such a situation, one
can generate different amides from the same pool of esters, which
will save time and cost of synthesis.
We were interested to study the reactivity of benzyl esters with
different types of amines. Therefore, we applied the optimized
BnNH2 (3 eq.)
OBn
NHBn
CbzHN
CbzHN
Incubator Shaker
40 oC
O
O
We have described a method of preparation of amides of N-pro-
tected amino acids with amines at 40 °C without any catalyst and
solvent achieving good yield. We could recover excess amine and
2.5 h, 78%
Scheme 1. Synthesis of benzyl amide from benzyl ester of Cbz-glycine.