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Chemistry Letters Vol.37, No.12 (2008)
Direct Preparation of Primary Amides by Reaction of Carboxylic Acids
and Ammonia in Alcohols Using DMT-MM
Tsukasa Mizuhara,2 Kazuhito Hioki,2;3 Megumi Yamada,2 Hideaki Sasaki,2 Daiki Morisaki,1 and Munetaka Kunishimaꢀ1;3
1Faculty of Pharmaceutical Sciences, Institute of Medical, Pharmaceutical, and Health Sciences,
Kanazawa University, Kakuma-machi, Kanazawa 920-1192
2Faculty of Pharmaceutical Sciences, Kobe Gakuin University, 1-1-3 Minatojima, Chuo-ku, Kobe 655-8586
3Life Science Center, Kobe Gakuin University, 1-1-3 Minatojima, Chuo-ku, Kobe 655-8586
(Received September 2, 2008; CL-080833; E-mail: kunisima@p.kanazawa-u.ac.jp)
A simple and mild method for the direct conversion of car-
boxylic acids to primary amides has been developed by using 4-
(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chlo-
ride (DMT-MM). The reaction proceeds by adding DMT-MM to
a mixture of carboxylic acids and an ammonia source in metha-
nol, 2-propanol, or THF without any additives. The present
method is quite practical in that aqueous ammonia or ammonium
chloride/triethylamine can be used as an ammonia source. Meth-
anol or 2-propanol is an ideal polar solvent because it is inexpen-
sive, can be removed by rotary evaporator, and solubilizes many
kinds of polar or nonpolar compounds.
ploys 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholini-
um chloride (DMT-MM).
We previously showed that a new coupling reagent, DMT-
MM, was useful for the preparation of secondary and tertiary
amides.17–19 The coupling reaction between various carboxylic
acids and primary or secondary amines occurs readily at room
temperature in water, alcohol, and other aqueous solvents as well
as in common aprotic organic solvents, such as THF and di-
chloromethane.17–20 In early studies, we attempted to prepare
primary amides using aqueous ammonia solution, readily avail-
able from commercial sources, in water. We were disappointed,
however, that, the reaction of 3-phenylpropionic acid (1a) gave
only a moderate yield (63%) of the desired primary amide 2a,
even though an excess of ammonia (2.5 equiv) was used, as
shown in eq 1. We presume this result was due to the weak nu-
cleophilicity of ammonia compared to primary and secondary
amines. In addition, strong hydration of ammonia in water
may depress the reaction. As a result, hydrolysis of the activated
acyl intermediate (acyl triazine) would competitively take place.
Thus, DMT-MM seemed to be unsuitable for preparation of pri-
mary amides.
After several years, we found that the yield of primary
amides using DMT-MM was much improved by using a metha-
nol solution of ammonia. As shown in eq 2, when an amino acid
1b was treated with ammonia (3.0 equiv) dissolved in methanol
and DMT-MM (1.5 equiv) in THF as a solvent, 2b was obtained
in 95% yield. Similarly, 1c gave 2c in 97% yields under the same
conditions. Because hydrogen bonds formed in methanol are
weaker than those in water,21 ammonia in methanol may have
the sufficient nucleophilicity to form primary amides. Encour-
aged by the result, we again attempted to establish a mild and
practical method for the direct preparation of primary amides
from carboxylic acids by DMT-MM. Preliminary reactions were
performed in methanol with 1a as a model substrate, and a com-
mercially available methanol solution of ammonia was used. As
shown in Table 1, Entry 1, treatment of a mixture of 1a (1.0
equiv) and ammonia (1.5 equiv) with DMT-MM (1.2 equiv) in
methanol for 4 h at room temperature gave 2a in 90% yield.
Since both methanol and ammonia can be readily removed by
evaporation, the work-up procedure could be simple. We next
A variety of mild one-step dehydrocondensation methods
have been developed for synthesizing secondary and tertiary
amides from carboxylic acids and amines.1–3 In contrast, reports
of a similar coupling between carboxylic acids and ammonia
leading to the formation of primary amides are limited, and
therefore, an efficient and convenient method is still being
sought. The specific chemical and physical properties of ammo-
nia constitute disadvantages for its use; a weak basicity (the pKa
value of the conjugate acid is 9.2), a low boiling point (ꢁ33 ꢂC;
it is gaseous at ordinary temperatures and pressures), and high
water solubility. Since dehydrocondensation is generally con-
ducted in a less polar aprotic solvent under dry conditions, sour-
ces of ammonia in the form of a gas, an aqueous solution, or a
polar salt would not be suitable here. In traditional thermal meth-
ods for direct conversion of carboxylic acids into primary
amides, a mixture of the acids and ammonia or its derivatives
are heated at high temperature (around 200 ꢂC) for several
hours.4–7 Activated derivatives of carboxylic acids, such as acid
chlorides, acid anhydrides, or activated esters reportedly under-
go coupling even with aqueous ammonia.4,8–13 Unless the acti-
vated acid-derivatives are commercially available, a separate
step is required for their preparation.
Wang and McMurray reported a simple and more practical
method that uses a combination of ammonium chloride (NH4Cl),
DIPEA, HOBt, and typical peptide coupling agents (PyBOP,
HBTU, EDCA, and DCC).14,15 Recently, HOTT or TOTT were
reported as being more efficient agents that can be used under
similar conditions.16 Since these reagents enable the activation
of carboxylic acid in the presence of ammonia, the reaction pro-
cedure is very simple. The former reaction requires expensive
HOBt as an additive while the latter does not. The solvent em-
ployed in both the reactions is DMF which however is not very
easy to use because of its high boiling temperature (153 ꢂC). In
this letter, we report a simple, inexpensive, and mild method for
preparation of primary amides from carboxylic acid that em-
Table 1. Yield of 2a when prepared in a methanol solvent using dif-
ferent sources of ammonia
Entry
Source of ammonia
Yield/%a
1
2
3
NH3 in MeOH
NH3 in H2O
NH4Cl/Et3N
90
92
93
aIsolated yield.
Copyright Ó 2008 The Chemical Society of Japan