Development of a process for triazine-promoted amidation of carboxylic acids

Article abstract of DOI:10.1021/op980097y

A process has been developed for the triazine-promoted amidation of carboxylic acids. We have identified 2,4,6-trichloro-1,3,5-triazine (cyanuric chloride) as a cost-effective reagent for this transformation. The procedure is a suitable alternative to traditional amidation processes when an acid chloride cannot be prepared from the corresponding carboxylic acid due to safety, stability, or handling concerns.

Full text of DOI:10.1021/op980097y

Organic Process Research & Development 1999, 3, 172−176
Development of a Process for Triazine-Promoted Amidation of Carboxylic Acids
Heather L. Rayle* and Lisa Fellmeth
Research Laboratories, Rohm and Haas Company, Spring House, PennsylVania 19477
Abstract:
Because of the disadvantages associated with the use of
acid chlorides and anhydrides in amidation reactions, ami-
dation of carboxylic acids is an active area of research. A
common approach involves treatment of the acid with a
reagent to form an activated intermediate, which is then
treated with an amine in situ to form the amide product. This
approach is primarily of interest for the preparation of
peptides. Many reagents have been identified that allow
coupling of carboxylic acids and amines. However, most are
quite expensive, and separation of the byproducts produced
is difficult.
We have developed a process suitable for large-scale
preparation of amides using carboxylic acids and a triazine
reagent as the promoter. While our interest is in the
preparation of amides which have activity as agrochemicals,
the work may have peptide synthesis applications as well.
A process has been developed for the triazine-promoted ami-
dation of carboxylic acids. We have identified 2,4,6-trichloro-
1,3,5-triazine (cyanuric chloride) as a cost-effective reagent for
this transformation. The procedure is a suitable alternative to
traditional amidation processes when an acid chloride cannot
be prepared from the corresponding carboxylic acid due to
safety, stability, or handling concerns.
Introduction
Amides are typically prepared by coupling an amine with
an acid chloride generated from the parent carboxylic acid.
While acid chlorides are highly reactive reagents, they suffer
from several disadvantages. When an acid chloride is not
commercially available, its manufacture can present handling
and safety concerns. Though technically simple, conversion
of a carboxylic acid to the corresponding acid chloride can
be cumbersome in a plant. The acid chloride is often
generated from an acid derivative such as an ester as part of
a multistep synthesis; in this case, the carboxylic acid
intermediate must be filtered and dried or extracted into a
suitable solvent and dried azeotropically. These steps add
cost through increased cycle times.
The typical reagents employed to prepare an acid chloride
from a carboxylic acid are corrosive (thionyl chloride) or
toxic (phosgene). While these reagents are inexpensive and
very useful in the preparation of many acid chlorides, there
are some situations in which these reagents are unsuitable.
Certain carboxylic acids, such as some optically active
compounds, are unstable to acidic conditions. Additionally,
some smaller manufacturing facilities such as pilot plants
may not have the facilities or the desire to handle toxic or
highly corrosive reagents. Acid chlorides also present
handling and storage issues due to their corrosivity and water
reactivity.
Acid anhydrides have been utilized as alternatives to acid
chlorides in amidation procedures. However, this procedure
is often problematic. If the carboxylic acid is converted to a
symmetric anhydride, 1 equiv of carboxylic acid is lost as
the byproduct of the amidation reaction. While expensive
acids may be isolated and reconverted to anhydride, the
additional processing required may be costly. If the acid is
sufficiently expensive, a mixed anhydride may be prepared
from an inexpensive material such as acetic acid. However,
it is unlikely that only one of the acid components will couple
with the amine, and a mixture of amide products is often
obtained.
Results and Discussion
Very few reagents reported to promote amidation of
carboxylic acids are suitable for adaptation to large-scale
manufacture. Many of the known reagents are costly,
particularly those developed for the synthesis of peptides.
Additionally, separation of the byproduct produced from the
activating reagent is difficult unless chromatographic tech-
niques are employed. The most economically viable reagent
disclosed in the literature is 2-chloro-4,6-dimethoxy-1,3,5-
triazine.1 The reagent is commercially available and is readily
prepared from commercially available 2,4,6-trichloro-1,3,5-
triazine (cyanuric chloride) using methanol and aqueous
base.2 When treated with equimolar amounts of a carboxylic
acid and a tertiary amine base, the activated species shown
in Scheme 1 is formed.3 This intermediate reacts with an
amine to form the amide and an insoluble hydroxytriazine
byproduct, which is readily removed by filtration.
Our investigation began with an evaluation of the reaction
conditions reported in the literature for amide formation using
2-chloro-4,6-dimethoxy-1,3,5-triazine. A carboxylic acid of
interest, 3,5-dichloro-4-methylbenzoic acid, was combined
with the triazine reagent and N-methylmorpholine at ambient
temperature. The intermediate was treated with several
amines, affording the desired amides cleanly and in good
yield (Table 1).
Once the dimethoxytriazine reagent was proven to be an
effective amidation promoter, we set out to improve upon
(1) (a) Kaminski, Z. J. Tetrahedron Lett. 1985, 26, 2901. (b) Kaminski, Z. J.
Synthesis 1987, 917. (c) Taylor, E. C.; Schrader, T. H.; Walensky, L. D.
Tetrahedron 1992, 48, 19.
(2) (a) Menicagli, R.; Malanga, C.; Peluso, P. Synth. Commun. 1994, 24, 2153
and references therein. (b) Cronin, J. S.; Ginah, F. O.; Murray, A. R.; Copp,
J. D. Synth. Commun. 1996, 26, 3491.
(3) Kaminski, Z. J.; Paneth, P.; Rudzinski, J. J. Org. Chem. 1998, 63, 4248.
172
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10.1021/op980097y CCC: $18.00 © 1999 American Chemical Society and Royal Society of Chemistry
Published on Web 03/31/1999

Scheme 1. General scheme for amidation of carboxylic
acids with dimethoxytriazine reagent
Scheme 2. General scheme for amidation of carboxylic
acids with cyanuric chloride
Table 1. Amidation of 3,5-dichloro-4-methylbenzoic acid
promoted by 2-chloro-4,6-dimethoxy-1,3,5-triazine
time yield
triazine derivative. Based on these results, our proposed
intermediate is the triacylated triazine shown in Scheme 2.
The nature of the base used to generate the carboxylate
salt was not critical. While tertiary amine bases were
effective, we preferred to develop a procedure employing
an inorganic base. Aqueous sodium hydroxide was suitable,
and the presence of water did not adversely affect intermedi-
ate formation. It should be noted that the sodium hydroxide
was depleted by adding the carboxylic acid before the triazine
reagent in order to avoid hydroxytriazine formation. The
intermediate formed rapidly, as evidenced by precipitate
formation and heat evolution upon addition of the triazine
to the carboxylate salt. We also utilized preformed carboxy-
late salts in the reaction, demonstrating that base is not
required for this procedure. This modification is useful when
the desired substrate is a commercially available carboxylate
salt or when it is necessary to isolate the salt due to
purification or other handling considerations. Upon addition
of a primary amine, a second exotherm was observed;
amidation was typically complete within 1 h. A summary
of the experimental data appears in Table 2.
amine
product (h)
(%)
tert-octylamine
1
2
3
1
6
1
72
68
73
3-amino-1-chloro-3-methylpentan-2-one
3-amino-3-ethylpentyne
the reported reaction conditions to develop a process suitable
for large-scale synthesis. First, we examined the utility of
cyanuric chloride, the commercially available parent com-
pound of the dimethoxytriazine reagent, as an amidation
promoter. We theorized that use of the trichlorotriazine
promoter would permit the use of only 0.33-0.5 mol of
triazine reagent per mole of carboxylic acid employed. We
found several references to the use of cyanuric chloride for
amidation,4 but the procedures were not well suited to scale-
up. The triazine reagent and carboxylic acid were typically
employed in a 1:1 ratio, which circumvents the advantage
of employing the trichlorotriazine reagent. In each case,
tertiary amine bases were used to generate the activated
intermediate. These conditions were undesirable from cost
and waste generation considerations.
The cyanuric chloride-promoted process has several
advantages that make it suitable for large-scale manufacture
of amides. The ability to use only 0.33 equiv of the triazine
promoter is advantageous because it minimizes reagent
utilization and byproduct generation compared to the
dimethoxytriazine procedure. The reaction is robust, as the
presence of water in both the activation and amidation steps
is tolerated. This is an important feature for two reasons.
First, inexpensive inorganic bases may be used to generate
the carboxylate anion required in the activation step. This
improvement simplifies the byproduct streams; we have
eliminated the amine bases used in the literature which would
have to be disposed of or recycled. The water tolerance of
the procedure is also desirable because some amines of
interest are isolated as solutions in solvent-water azeotropes.
Another advantage of the process is that separation of the
byproduct is simple. The precipitated cyanuric acid is readily
separated by filtration, while the amide product remains in
We also found that there was some disagreement in the
literature regarding the product of the reaction between
cyanuric chloride and a carboxylic acid. It has been proposed
that the product of this reaction is the corresponding acid
chloride. If this were the case, this amidation procedure
would be undesirable for racemizable substrates such as
amino acids due to the presence of the hydrogen chloride
byproduct. However, in our hands, no acid chloride was
observed after the activation step. We successfully performed
the amidation using 0.33 equiv of cyanuric chloride per mole
of carboxylic acid. The experimental procedure was other-
wise similar to that employed when using the dimethoxy-
(4) (a) Venkataraman, K.; Wagle, D. R. Tetrahedron Lett. 1979, 3037. (b)
Wagle, D. R.; Garai, C.; Chiang, J.; Monteleone, M. G.; Kurys, B. E.;
Strohmeyer, T. W.; Hegde, V. R.; Manhas, M. S.; Bose, A. K. J. Org. Chem.
1988, 53, 4227 and references therein. (c) Sainsbury, M.; Strange, R. H.;
Woodward, P. R.; Barsanti, P. A. Tetrahedron 1993, 49, 2065. (d) Hinz,
W.; Just, G. Can. J. Chem. 1987, 65, 1503.
Vol. 3, No. 3, 1999 / Organic Process Research & Development
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173

Table 2. Cyanuric chloride-promoted amidation of carboxylic acids
carboxylic acid/base
amine
product time (h) yield (%)
3,5-dichlorobenzoic acid, N-methylmorpholine (NMM) 3-amino-3-methylbutyne (aqueous solution)
4
5
6
6
7
8
1
1
2
0.5
1
69
73
72
75
65
44
propionic acid, NMM
3,4-dichloroaniline
3,5-dichloro-4-methylbenzoic acid, NMM
3,5-dichloro-4-methylbenzoic acid, NaOH
potassium benzoate, no added base
potassium benzoate, no added base
3-amino-3-methylpentyne (aqueous solution)
3-amino-3-methylpentyne (aqueous solution)
tert-octylamine
3-amino-3-methylpentyne (aqueous solution)
0.5
solution. Residual cyanuric acid can be removed with a base
wash. Another attractive feature of this process is that
amidation occurs readily, even when sterically hindered
primary tert-alkylamines are employed in the reaction.
While the yields achieved to date are acceptable (typically
65-75%), they do not currently match yields obtained from
traditional amidation methods. Occasionally, unreacted car-
boxylic acid is observed in the reaction mixture and removed
with a base wash. No side products are observed in most
cases, indicating that yield losses occur during workup. We
believe that the losses are occurring during filtration, when
product is trapped with the cyanuric acid byproduct. These
losses can be minimized by effective deliquoring and
washing during solid-liquid separation of the byproduct and
the solution containing the amide product.
slurry was cooled to room temperature and filtered. The solid
was washed with a minimal amount of solvent; the filtrates
were combined and washed with 1 M sodium hydroxide
solution and with water. The organic layer was dried over
sodium sulfate, and the solvent was removed by evaporation
under reduced pressure. The residue was dried under vacuum
to yield the amide product.
3,5-Dichloro-4-methyl-N-(1,1,3,3-tetramethylbutyl)-
benzamide (1). Following the general procedure, a slurry
of the carboxylic acid in acetonitrile (20 mL) was treated
with the triazine reagent and amine base. The resulting slurry
was treated with tert-octylamine (1.32 g, 10.24 mmol) at
ambient temperature for 1 h. Workup as described above
afforded the amide as a white solid (2.21 g, 72%): mp 150-
1
152 °C; H NMR (DMSO-d6) δ 7.85 (s, 2H), 2.44 (s, 3H),
1.84 (s, 2H), 1.41 (s, 6H), 0.95 (s, 9H); 13C NMR (DMSO-
d6) δ 163.1, 136.0, 135.6, 134.3 (2C), 126.6 (2C), 54.8, 49.2,
31.3, 31.0, 29.4, 17.2; MS (CI) m/z 316 (M + H). Anal.
Calcd for C16H23Cl2NO: C, 60.76; H, 7.33; N, 4.43; Cl,
22.42. Found: C, 60.82; H, 7.12; N, 4.38; Cl, 22.21.
Conclusions
The amidation of carboxylic acids promoted by triazine
reagents is an alternative to traditional amidation procedures
employing acid chlorides. We have developed a process for
this transformation which utilizes 2,4,6-trichloro-1,3,5-tri-
azine (cyanuric chloride) as the activating agent. The ability
to avoid the preparation and handling of acid chlorides and
the ease of byproduct separation are key features of this
chemistry.
1
Experimental Section
3,5-Dichloro-N-(3-chloro-1-ethyl-1-methyl-2-oxopropyl)-
4-methylbenzamide (2).5 Following the general procedure,
a slurry of the carboxylic acid in tert-butyl methyl ether (35
mL) was treated with the triazine reagent and amine base.
Addition of 3-amino-1-chloro-3-methylpentan-2-one hydro-
chloride6 (1.85 g, 9.94 mmol) and N-methylmorpholine (3.5
mL) afforded a slurry, which was stirred for 6 h at 55 °C.
Workup yielded the amide (2.24 g, 68%) as a white solid:
mp 158-160 °C (lit.7 mp 157-158 °C).
General Information. Solvents and reagents were ob-
tained from commercial sources and used without purification
unless otherwise indicated. Gas chromatography was per-
formed using a Hewlett-Packard 5890A chromatograph
equipped with a flame ionization detector. 1H and 13C NMR
were measured at 400 and 100 MHz, respectively, using
tetramethylsilane as an internal standard. Melting points are
uncorrected.
General Procedure for 2-Chloro-4,6-dimethoxy-1,3,5-
triazine-Promoted Amidation of 3,5-Dichloro-4-methyl-
benzoic Acid. A slurry of 3,5-dichloro-4-methylbenzoic acid
(2.0 g, 9.75 mmol) in a polar organic solvent was treated
with 2-chloro-4,6-dimethoxy-1,3,5-triazine (1.71 g, 9.75
mmol) and N-methylmorpholine (1.01 g, 9.94 mmol). A
slight exotherm (1-2 °C) was observed, and most of the
solids dissolved. The reaction mixture thickened noticeably
after 20-40 min. After the mixture was stirred for 1 h at
ambient temperature, the amine reagent (1.02-1.05 equiv)
was added, and a second exotherm of 2-4 °C occurred. The
reaction was stirred at the temperature noted and was judged
to be complete by GC analysis of the reaction mixture. The
2
3,5-Dichloro-N-(1,1-diethyl-2-propynyl)-4-methylbenz-
amide (3). Following the general procedure, a slurry of the
(5) Michelotti, E. L.; Young, D. H. U.S. Patent 5304572, 1994.
(6) Michelotti, E. L.; Rayle, H. L.; Stephens, R. W.; Zabrodski, W. J. U.S.
Patent 5874466, 1999.
(7) Rayle, H. L.; Roemmele, R. C.; Stephens, R. W. U.S. Patent 5859254, 1999.
174
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carboxylic acid in tert-butyl methyl ether (35 mL) was treated
with the triazine reagent and amine base. The resulting slurry
was treated with 3-amino-3-ethylpentyne (1.11 g, 9.94 mmol)
and stirred at 55 °C for 1 h. Workup afforded the amide as
N-(3,4-Dichlorophenyl)propionamide (5).10 Following
the general procedure, a solution of propionic acid (10.0 g,
134.99 mmol) in n-butyl acetate (100 mL) was treated with
2,4,6-trichloro-1,3,5-triazine (8.30 g, 44.99 mmol) and N-
methylmorpholine (13.93 g, 137.7 mmol). The resulting
slurry was treated with 3,4-dichloroaniline (22.31 g, 137.7
mmol), and the reaction mixture was stirred at 23 °C for 1
h. Workup afforded the amide as a pale tan solid (21.54 g,
73%): mp 86-88 °C (lit.11 mp 86-91 °C). The spectral
data obtained were identical with those of an authentic
sample.
1
a white solid (2.12 g, 73%): mp 122-124 °C; H NMR
(DMSO-d6) δ 8.21 (bs, 1H), 7.89 (s, 2H), 3.24 (s, 1H), 2.44
(s, 3H), 1.98 (dq, 4H, J ) Hz), 0.94 (t, 3H, J ) Hz); 13C
NMR (DMSO-d6) δ 163.0, 136.4, 134.5, 134.3 (2C), 126.9
(2C), 85.2, 73.6, 55.8, 29.7 (2C), 17.2, 8.4 (2C); MS (CI)
m/z 298 (M + H). Anal. Calcd for C15H17Cl2NO: C, 60.41;
H, 5.75; N, 4.70; Cl, 23.78. Found: C, 60.28; H, 5.41; N,
4.63; Cl, 23.66.
5
3,5-Dichloro-N-(1-ethyl-1-methyl-2-propynyl)-4-meth-
ylbenzamide (6). Following the general procedure, a slurry
of 3,5-dichloro-4-methylbenzoic acid (2.5 g, 12.19 mmol)
in n-butyl acetate (40 mL) was treated with 2,4,6-trichloro-
1,3,5-triazine (0.74 g, 4.02 mmol) and N-methylmorpholine
(1.26 g, 12.43 mL). The resulting slurry was treated with
3-amino-3-methylpentyne (1.63 g of a 74% solution in water,
12.43 mmol) and stirred at 23 °C for 2 h. Workup gave the
amide as a white solid (2.50 g, 72%): mp 119-120 °C; 1H
NMR (DMSO-d6) δ 8.32 (bs, 1H), 7.89 (s, 2H), 3.18 (s, 1H),
2.44 (s, 3H), 1.95 (dq, 2H, J ) Hz), 1.56 (s, 3H), 0.95 (t,
3H, J ) Hz); 13C NMR (DMSO-d6) δ 162.9, 136.5, 134.4,
134.4 (2C), 126.8 (2C), 86.4, 72.4, 51.1, 32.5, 26.0, 17.2,
8.5; MS (CI) m/z 284 (M + H). Anal. Calcd for C14H15Cl2-
NO: C, 59.17; H, 5.32; N, 4.93; Cl, 24.95. Found: C, 59.02;
H, 5.09; N, 4.97; Cl, 25.02.
3
General Procedure for 2,4,6-Trichloro-1,3,5-triazine-
Promoted Amidation Using N-Methylmorpholine as Base.
A slurry of the carboxylic acid (1 equiv) in a polar organic
solvent was treated with 2,4,6-trichloro-1,3,5-triazine (0.33
equiv) and N-methylmorpholine (1.02 equiv). A 12-13 °C
exotherm was observed, and a precipitate formed upon
addition of the amine base. After the slurry was stirred for
1 h, the primary amine (1.02-1.05 equiv) was added; a 3-5
°C exotherm was observed. The reaction was judged to be
complete by GC analysis. The slurry was cooled to room
temperature and filtered. The solid was washed with a
minimal amount of solvent. The filtrates were combined and
washed with 1 M sodium hydroxide solution and with water.
The organic layer was dried over sodium sulfate, and the
solvent was removed by evaporation under reduced pressure.
The residue was dried under vacuum to yield the amide
product.
3,5-Dichloro-N-(1,1-dimethyl-2-propynyl)benzamide (4).8
Following the general procedure, a slurry of 3,5-dichlo-
robenzoic acid (2.0 g, 10.47 mmol) in n-butyl acetate (35
mL) was treated with 2,4,6-trichloro-1,3,5-triazine (0.64 g,
3.49 mmol) and N-methylmorpholine (1.08 g, 10.68 mmol).
The resulting slurry was treated with 3-amino-3-methylbu-
tyne (0.99 g of a 90% solution in water, 10.68 mmol) and
stirred at 23 °C for 1 h. Workup as described above afforded
the amide as a white solid (1.86 g, 69%): mp 154-156 °C
(lit.9 mp 155-157 °C). The spectral data obtained were
identical with those of an authentic sample.
6
3,5-Dichloro-N-(1-ethyl-1-methyl-2-propynyl)-4-meth-
ylbenzamide (6): Carboxylate Formation Using Aqueous
Inorganic Base. Sodium hydroxide (9.75 mL of a 1 M
solution, 9.75 mmol) was added to a slurry of 3,5-dichloro-
4-methylbenzoic acid (2.0 g, 9.75 mmol) in acetonitrile (40
mL). A 4 °C endotherm was observed. The reaction mixture
was stirred for 2 h, and then 2,4,6-trichloro-1,3,5-triazine
(0.59 g, 3.22 mmol) was added. The resulting slurry was
stirred for 2 h and treated with 3-amino-3-methylpentyne
(1.34 g of a 74% solution in water, 10.24 mmol); a 3 °C
exotherm was observed. The reaction was stirred at 23 °C
for 2 h and worked up as described in the general procedure
to give the amide as a white solid (2.09 g, 75%). The spectral
data obtained matched those listed above.
4
(8) Propyzamide, manufactured and marketed as Kerb herbicide by Rohm and
Haas Co., Philadelphia, PA.
(10) Propanil, manufactured and marketed as Stam herbicide by Rohm and Haas
Co., Philadelphia, PA.
(9) Swithenbank, C.; McNulty, P. J.; Viste, K. L. J. Agric. Food Chem. 1971,
19, 417.
(11) Schaefer, W.; Wegler, R. French Patent FR 1339155, 1963; Chem. Abstr.
1964, 60, 2861a.
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175

N-(1,1,3,3-Tetramethylbutyl)benzamide (7):12 Amida-
tion Using Carboxylate Salt without Added Base. A slurry
of potassium benzoate (2.0 g, 12.48 mmol) in 40 mL of 7:1
acetonitrile-water was treated with 2,4,6-trichloro-1,3,5-
triazine (0.76 g, 4.12 mmol). The mixture was stirred for 1
h, and tert-octylamine (1.69 g, 13.10 mmol) was added. A
4 °C exotherm was observed. The reaction was stirred at 23
°C for 1 h. Workup as described in the general procedure
afforded the amide as a white solid (1.92 g, 65%): mp 63-
65 °C (lit.13 mp 67-69 °C).
N-(1-Ethyl-1-methyl-2-propynyl)benzamide (8):14 Ami-
dation Using Carboxylate Salt without Added Base. A
slurry of potassium benzoate (2.0 g, 12.48 mmol) in 35 mL
of 4:1 acetonitrile-water was treated with 2,4,6-trichloro-
1,3,5-triazine (0.76 g, 4.12 mmol). A 2 °C exotherm was
observed. The mixture was stirred for 1 h, and 3-amino-3-
methylpentyne (1.72 g of a 74% solution, 13.10 mmol) was
added. The reaction was stirred at 23 °C for 0.5 h. Workup
as described in the general procedure afforded the amide as
a white solid (1.08 g, 44%): mp 105-107 °C (lit.14 mp 106-
107 °C).
8
7
Received for review December 17, 1998.
OP980097Y
(12) (a) Lacey, R. N. J. Chem. Soc. 1960, 1633. (b) Alender, J.; Morgan, P.;
Timberlake, J. J. Org. Chem. 1983, 48, 755.
(13) Johnson, R. A.; Murray, H. C.; Reineke, L. M. J. Am. Chem. Soc. 1971,
93, 4872.
(14) Hennion, G. F.; Teach, E. G. J. Am. Chem. Soc. 1953, 75, 1653.
176
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