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Chemistry Letters Vol.37, No.5 (2008)
Tetrabenzylpyrophosphate: An Efficient Catalyst for the Synthesis of Carboxamides
from Carboxylic Acids and Amines
Y. Thirupathi Reddy, P. Narsimha Reddy, P. Raghotham Reddy, and Peter A Crooksꢀ
Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536, USA
(Received February 14, 2008; CL-080169; E-mail: pcrooks@email.uky.edu)
An efficient method for the synthesis of simple and sterically
When 1.1 moles of TBPP and 2.1 moles of DMAP were used, the
reaction was complete within 1 h to furnish the desired carbox-
amide i.e., 4-phenoxy-N-(2-phenylethyl)butanamide, in 95%
yield (Entry 1). Furthermore, the effect of different activators
was examined. Thus, 4-pyrrolidinopyridine (PPY), N-methyl-
imidazole, and N-butylimidazole were also each successfully
employed in this reaction as alternative activators to DMAP
and afforded the desired carboxamide in good yield (Entries
2–4). The use of tertiary amines, such as triethylamine and
ethyldiisopropylamine, as activators in such coupling reactions
also afforded the desired carboxamide in moderate yield (Entries
5 and 6). The use of 1-hydroxybenzotriazole (HOBt), resulted
in a decrease in the yield of the desired carboxamide to only
52% (Entry 7).
The stoichiometry of DMAP and TBPP was also examined
(Table 2). The desired carboxamide was formed in quantitative
yield when 1.1 to 2.2 molar ratio of TBPP and DMAP was
utilized (Entry 1).8 Interestingly, a slight deviation from this
molar ratio had a significant effect on yield. Thus, a 1.1 to 2.1
molar ratio of TBPP and DMAP afforded a reduced yield of
89% of the desired carboxamide (Entry 2). The yield of carbox-
amide decreased to 72% when a 1.1 to 1.2 molar ratio of TBPP
and DMAP was used (Entry 3).
The effect of different solvents was also examined (Table 3).
The reaction proceeded smoothly in both nonpolar solvents such
as CHCl3, CH2Cl2, or toluene, and in polar solvents such as
THF, DMF, or MeCN to afford the desired carboxamide in ex-
cellent yields (Entries 1 and 3–7). It was also observed that the
yield of the carboxamide decreased to 83% when the reaction
was carried out in CHCl3 at 0 ꢁC (Entry 2).
Examples of the synthesis of carboxamides from the
coupling of various carboxylic acids and amines utilizing
TBPP/DMAP under optimized conditions are listed in Table 4.
The condensation reaction of 4-phenoxybutyric acid with pri-
hindered carboxamides from various carboxylic acids and
amines using tetrabenzylpyrophosphate (TBPP) as a coupling
agent in the presence of 4-(dimethylamino)pyridine (DMAP)
is described. The reaction is operationally straightforward, pro-
ceeds under mild conditions at room temperature, and affords
the desired product in high yield.
The synthesis of carboxamides is one of the most fundamen-
tal and important processes in organic and medicinal chemistry
for producing natural and unnatural bioactive compounds such
as peptides, ꢀ-lactams, and macrolactams, and to date, various
efficient coupling or dehydration methods for the synthesis of
carboxamides have been reported.1–4 The use of tetraethylpyro-
phosphate is known in the literature for the synthesis of carbox-
amides,5 and very recently, Mukaiyama et al. have reported the
synthesis of carboxamides using benzenesulfonic anhydride as
an efficient catalyst.6 Although many coupling reagents that
afford carboxamides have been investigated, there remain disad-
vantages, including low yields due to increasing amounts of
by-product, prolonged reaction times, use of toxic reagents and
tedious workup procedures, which necessitate the development
of an alternative route for the synthesis of biologically and
commercially important carboxamide derivatives.
The above observations prompted us to consider the use of
tetrabenzylpyrophosphate (TBPP, Figure 1) for the synthesis
of various simple and sterically hindered carboxamides. TBPP
can be easily prepared from inexpensive dibenzylphosphate.7
To the best of our knowledge, the use of TBPP as a dehydrating
agent for the synthesis of carboxamides from carboxylic acids
and amines has not been reported. Pyrophosphates are well
known as phosphorylation agents. Hence, phosphorylated
carboxylic acid mixed anhydrides are expected to be active
intermediates in the formation of carboxamides from amines.
We now report a new and efficient method for the synthesis
of carboxamides from corresponding carboxylic acids and
amines using TBPP as a coupling reagent in the presence of
DMAP as a promoter.
Table 1. Effect of activating agents on carboxamide yield
Intially, the condensation of 4-phenoxybutyric acid with 2-
phenylethylamine in the presence of TBPP and DMAP in CHCl3
at room temperature was examined as a model reaction (Table 1).
Entry
Activator
Yielda/%
1
2
3
4
5
6
7
DMAP
PPY
95
89
92
90
75
79
52
N-Methylimidazole
N-Butylimidazole
Triethylamine
Diisopropylamine
HOBt
Figure 1. Tetrabenzylpyrophosphate (TBPP).
aIsolated yield.
Copyright Ó 2008 The Chemical Society of Japan