Sustainable triazine-based dehydro-condensation agents for amide synthesis

Article abstract of DOI:10.3390/molecules26010191

Conventional methods employed today for the synthesis of amides often lack of economic and environmental sustainability. Triazine-derived quaternary ammonium salts, e.g., 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMTMM(Cl)), emerged as promising dehydro-condensation agents for amide synthesis, although suffering of limited stability and high costs. In the present work, a simple protocol for the synthesis of amides mediated by 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) and a tert-amine has been described and data are compared to DMTMM(Cl) and other CDMT-derived quaternary ammonium salts (DMT-Ams(X), X: Cl^? or ClO₄^?). Different tert-amines (Ams) were tested for the synthesis of various DMT-Ams(Cl), but only DMTMM(Cl) could be isolated and employed for dehydro-condensation reactions, while all CDMT/tert-amine systems tested were efficient as dehydro-condensation agents. Interestingly, in best reaction conditions, CDMT and 1,4-dimethylpiperazine gave N-phenethyl benzamide in 93% yield in 15 min, with up to half the amount of tert-amine consumption. The efficiency of CDMT/tert-amine was further compared to more stable triazine quaternary ammonium salts having a perchlorate counter anion (DMT-Ams(ClO₄)). Overall CDMT/tert-amine systems appear to be a viable and more economical alternative to most dehydro-condensation agents employed today.

Full text of DOI:10.3390/molecules26010191

molecules
Article
Sustainable Triazine-Based Dehydro-Condensation Agents for
Amide Synthesis
Roberto Sole 1 , Vanessa Gatto
2
, Silvia Conca 1 , Noemi Bardella , Andrea Morandini 1
1
and Valentina Beghetto 1
,2,
*
1
Dipartimento di Scienze Molecolari e Nanosistemi, Università Ca’ Foscari di Venezia, Via Torino 155,
0172 Venezia, Italy; roberto.sole@unive.it (R.S.); silvia.conca@unive.it (S.C.); noemi.bardella@unive.it (N.B.);
3
andrea.morandini@unive.it (A.M.)
Crossing srl, Viale della Repubblica 193/b, 31100 Treviso, Italy; vanessa.gatto@unive.it
Correspondence: beghetto@unive.it; Tel.: +39-041-2348928
2
*
Abstract: Conventional methods employed today for the synthesis of amides often lack of
economic and environmental sustainability. Triazine-derived quaternary ammonium salts, e.g.,
4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMTMM(Cl)), emerged as
promising dehydro-condensation agents for amide synthesis, although suffering of limited stability
and high costs. In the present work, a simple protocol for the synthesis of amides mediated by
2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) and a tert-amine has been described and data are
compared to DMTMM(Cl) and other CDMT-derived quaternary ammonium salts (DMT-Ams(X), X:
−
−
Cl or ClO4 ). Different tert-amines (Ams) were tested for the synthesis of various DMT-Ams(Cl),
but only DMTMM(Cl) could be isolated and employed for dehydro-condensation reactions, while all
CDMT/tert-amine systems tested were efficient as dehydro-condensation agents. Interestingly, in best
reaction conditions, CDMT and 1,4-dimethylpiperazine gave N-phenethyl benzamide in 93% yield in
ꢀ
ꢁꢂꢀꢃꢄꢅꢆꢇ
15 min, with up to half the amount of tert-amine consumption. The efficiency of CDMT/tert-amine
ꢀ
ꢁꢂꢃꢄꢅꢆ
was further compared to more stable triazine quaternary ammonium salts having a perchlorate
Citation: Sole, R.; Gatto, V.; Conca, S.;
Bardella, N.; Morandini, A.; Beghetto, V.
Sustainable Triazine-Based
counter anion (DMT-Ams(ClO )). Overall CDMT/tert-amine systems appear to be a viable and more
economical alternative to most dehydro-condensation agents employed today.
4
Dehydro-Condensation Agents
for Amide Synthesis. Molecules
Keywords: CDMT; triazines; amide synthesis; sustainable dehydro-condensation agents
2
021, 26, 191. https://doi.org/
1
0.3390/molecules26010191
1
. Introduction
The synthesis of amides is among the most important reactions in organic chemistry and
biochemistry because of the widespread occurrence of amides in pharmaceuticals, peptides,
biologically active compounds, industrial polymers, detergents, and lubricants [ ]. Conse-
quently, many different physical [ ] and chemical protocols have been developed for the
synthesis of amides by dehydro-condensation of a carboxylic acid and an amine [ 13].
Catalytic routes for the preparation of amides have also been reported with the intent to
increase atom efficiency of the process [ 14]. An alternative metal-free synthetic route
Academic Editor: Narciso M. Garrido
Received: 8 December 2020
Accepted: 29 December 2020
Published: 2 January 2021
1–6
7
Publisher’s Note: MDPI stays neu-
tral with regard to jurisdictional clai-
ms in published maps and institutio-
nal affiliations.
8–
2
,
for the formation of amides has been recently proposed by Zhang et al. [15] by coupling
reaction of formamide with different carboxylic acids.
Albeit the strategic importance of this class of compounds, most methods commonly
employed for the synthesis of amides still lack both in economic and environmental
sustainability, have low atom efficiency, generate large quantities of hazardous waste
products, and require complicated purification steps [16–18].
In this frame, dehydro-condensation reactions are a well-known and consolidated
protocol for the synthesis of amides, although toxic dehydro-condensation agents are often
Copyright: © 2021 by the authors. Li-
censee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and con-
ditions of the Creative Commons At-
tribution (CC BY) license (https://
creativecommons.org/licenses/by/
used to promote the reaction [17,19]. For example, carbodiimides such as dicyclohexyl-
carbodiimide (DCC) or 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide chlorohydrate
4
.0/).
Molecules 2021, 26, 191. https://doi.org/10.3390/molecules26010191
https://www.mdpi.com/journal/molecules

Molecules 2021, 26, 191
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(
EDC) employed in combination with N-hydroxysuccinimide (NHS), have frequently been
employed for the scope (Figure 1) [20–23].
Figure 1. Chemical structures of various dehydro-condensation agents.
Hydroxybenzotriazole (HOBt) [24–26], 1-hydroxy-7-azabenzotriazole (HOAt) [27–29],
and uronium or guanidinium salt derivatives such as, e.g., hexafluorophosphate azaben-
zotriazole tetramethyl uronium (HATU), hexafluorophosphate benzotriazole tetramethyl
uronium (HBTU), hexafluorophosphate chlorobenzotriazole tetramethyl uronium (HCTU),
and 1-cyano-2-ethoxy-2-oxoethylidenaminooxy)-dimethylamino-morpholino-carbenium
hexafluorophosphate (COMU) (Figure 1) have also been efficiently used to promote
carbodiimide-mediated peptide coupling reactions [18,30], although with scarce environ-
mental and economic sustainability [ 10 31]. In fact, DCC and EDC lead to the formation
9,
,
of toxic by-products [17], while uronium derivatives may contain highly harmful hydrazide
impurities [19].
More stringent rules regulating the use and disposal of organic solvents and increas-
ingly restrictive EU directives on hazardous substances make the quest for greener and
more efficient products and processes increasingly important [17,18].
In this prospective, quaternary ammonium salts of 2-halo-4,6-dialkoxy-1,3,5-triazines,
e.g., 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMTMM(Cl)),
(
see Figure 2), represent a valid alternative for the formation of amide bonds both in or-
ganic and water solvent [20 21 32 39]. In the last years, DMTMM(Cl), commonly known as
DMTMM, has found many applications as dehydro-condensation agent for the synthesis of
amides and esters [36 40], collagen cross-linking [ 21 38], preparation of carboxymethylcel-
lulose based films [39], amine grafting on hyaluronan [20 40 41], and peptide synthesis [42].
Additionally, the synthesis of a library of 2-(4,6-dimethoxy-1,3,5-triazinyl)trialkyl ammo-
,
,
–
,
7
,
,
,
,
−
−
nium salts (DMT-Ams(X), X: Cl or ClO4 ) and their activity as dehydro-condensation
agents for the synthesis of amides, has been reported by Kunishima et al. [43] (Figure 2).
This work is a milestone in the understanding of triazine based-condensation agents and
their application in various fields of chemistry. Further interesting feature is that DMTMM
and DMT-Ams(X) all degrade forming 2,4-dimethoxy-6-hydroxy-1,3,5-triazine (DMTOH)
and the corresponding tertiary amine hydrochloric salt, which are nontoxic. Moreover,
DMTOH can be recovered and recycled to produce 2-chloro-4,6-dimethoxy-1,3,5-triazine
(
CDMT) or DMTMM (Figure 2) [37]. To date, one of the main limitations to large-scale use
of DMTMM and DMT-Ams(X) remains their reduced stability in solution [43,44].

Molecules 2021, 26, 191
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O
N
O
O
N
O
O
N
O
N
N
N
N
N
N
Cl
OH
N
O
Cl
CDMT
DMTOH
DMTMM
O
N
N
N
O
Am
X = Cl, ClO4
X
DMT-Ams
N
N
N
N
N
N
Am =
4
O
1-methylpiperidine
NMP
1
-methylpyrrolidine trimethylamine 1,4-dimethylpiperazine
TMA
NNDP
-methylmorpholine
NMM
MPD
Figure 2. Chemical structures of 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT), 2,4-dimethoxy-6-
hydroxy-1,3,5-triazine (DMTOH), 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chlo-
ride (DMTMM) and 2-(4,6-dimethoxy-1,3,5-triazinyl)trialkyl ammonium salts (DMT-Ams).
All this in mind, we believe that the use of isolated triazine quaternary ammonium
salts could be overcome by direct addition of a 2-halo-4,6-dialkoxy-1,3,5-triazine and a
tert-amine in the reaction mixture. This straightforward methodology would avoid the
synthesis of isolated DMT-Ams(X), reduce production complexity, and solvent use and
allow to achieve a library of dehydro-condensation agents, modulated according to specific
requirements. Nowadays, a few data are available on dehydro-condensation reactions
carried out with similar protocols [43
,
45] and often referring to very specific substrates in
rather limited reaction conditions [46
–
50]. Only recently, Kitamura [34] and Kunishima [35
]
reported a similar protocol for amide condensation reactions, albeit in the presence of
amido- or imido-chlorotriazines. To the best of our knowledge, no in-depth study has been
reported on the advantages derived from the use of different CDMT/tert-amine systems
compared to isolated DMT-Ams(X).
Our research group has long been involved in the study of innovative sustainable
processes for fine chemistry [51–54]. Recently, our studies have focused on the development
of new dehydro-condensation agents. Therefore, in this work we wish to report a systematic
comparison between the efficiency of CDMT/tert-amine systems and isolated DMT-Ams(X)
for the synthesis of amides.
Moreover, the possible advantages derived from the use of CDMT/tert-amine systems
were also analyzed.
2. Results and Discussion
The activity of CDMT/tert-amine systems for dehydro-condensation reactions has been
compared with the activity of the corresponding isolated DMT-Ams(X). DMT-Ams(X) have
been synthesized according to the standard protocol reported in the literature [43 55 57].
,
–
For example, DMTMM was prepared by reaction of one equivalent of 2-chloro-4,6-
dimethoxy-1,3,5-triazine (CDMT) and 1.2 equivalents of N-methyl morpholine (NMM) in
THF at room temperature for 1 h. After work up, DMTMM was recovered in 85–88% yield.
In the present work, the CDMT/tert-amine protocol foresees dissolution of 1.3 mmoles
of an acid (e.g., 1a) in the reaction solvent, followed by addition (within a few seconds) of
1
.3 mmoles of CDMT, 1.3 mmoles of a tert-amine, and 1.2 mmoles of an amine (e.g., 2a
)
(
Scheme 1).

Molecules 2021, 26, 191
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Scheme 1. Dehydro-condensation reaction for the synthesis of amide 3a.
The yield in amide 3a was monitored by GLC after 15 min and 1 h (see e.g., entry 1 of
Table 1). For a set of preliminary experiments, the reaction mixture was monitored by GLC
also after 24 h; since no significant difference was observed between the yield in amide 3a
after 1 and 24 h, unless otherwise stated, all further reactions were monitored within 1 h.
Table 1. Dehydro-condensation reaction between 1a and 2a by 2-chloro-4,6-dimethoxy-1,3,5-triazine
(
CDMT)/N-methyl morpholine (NMM) system or isolated 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-
methylmorpholinium (DMTMM) in different solvents.
Coupling Agent [a]
Yield (%) [b] (15/60 min)
Entry
Solvent
1
2
THF
THF
CDMT/NMM
DMTMM
74/78
80/89
3
4
CH OH
CDMT/NMM
DMTMM
93/95
98/99
3
CH OH
3
5
6
EtOH
EtOH
CDMT/NMM
DMTMM
92/95
98/99
7
8
CH CN
CDMT/NMM
DMTMM
78/82
58/66
3
CH CN
3
9
Acetone
Acetone
CDMT/NMM
DMTMM
82/83
73/97
1
0
1
1
1
2
CH Cl
CDMT/NMM
DMTMM
86/93
85/92
2
2
2
CH Cl
2
1
1
3
4
Toluene
Toluene
CDMT/NMM
DMTMM
69/90
65/72
45/52 [
c]
1
1
5
6
H O
H O
2
CDMT/NMM
DMTMM
2
49/53 [
c]
Reaction conditions: benzoic acid: 1.3 mmol, phenylethylamine: 1.2 mmol, Solvent: 6 mL, T: 25 C. [a] Coupling
◦
agent: 1.3 mmol of CDMT and 1.3 mmol of NMM were added; for isolated DMTMM, 1.3 mmol were used.
[b]
[c]
Yield of 3a was measured by GLC using mesitylene as internal standard. Yields were measured on weight
of 3a recovered after workup.
2.1. Influence of the Solvent on Dehydro-Condensation Reactions
Preliminarily investigations on the CDMT/tert-amine system were carried out by
using NMM as amine. The influence of the solvent on the CDMT/NMM dehydro-
condensation activity was tested employing benzoic acid 1a and phenylethylamine 2a as
standard substrates (Scheme 1). Relevant data are reported in Table 1 and compared with
data from analogous reactions carried out in the presence of isolated DMTMM. All data
reported in Table 1 are the mean values achieved for a set of at least three experiments
monitored after 15 min and 1 h.
Interestingly, after 15 min, the CDMT/NMM system afforded, in most of the organic
solvents used, the amide 3a in equivalent or even better yields compared to DMTMM.
In CH OH, almost quantitative yield of 3a was measured both with DMTMM (98%) and
3
CDMT/NMM (93%) by 15 min (entries 3 and 4, Table 1). Noteworthy, the use of an alcohol
(
entries 3–6, Table 1) as reaction solvent achieved 3a
( 90%) with very high selectivity,
≥
both by CDMT/NMM system and isolated DMTMM, and only traces of the corresponding
ester were detected. These data are in agreement with Kunishima work [58], where the
rate of nucleophilic attack of 2-phenylethylamine to 3-phenylpropionic acid (aminolysis)

Molecules 2021, 26, 191
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4
was found to be approximately 2
advantage compared to other dehydro-condensation agents such as EDC/NHS for which
yields and selectivity in similar reaction conditions are known to be poor [ 20]. Moreover,
×
10 times faster than methanolysis. This is a significant
6
,
the difference in reactivity of the amine functionality, compared to, e.g., -OH or -SH groups,
allows to carry out chemoselective dehydro-condensation reactions for the synthesis of
amides, starting from carboxylic acids or amines bearing also -OH or -SH functionalities,
as widely reported in the literature [58–61]. Additionally, when the amine contains both a
hydroxyl and an amine functional group, no ester by-product is observed confirming that
the reactivity of the amine functional group is by far much higher than that of the -OH group
so that no ester is formed in the presence of DMTMM [46,58,61] and other 1,3,5-triazine-
based dehydro-condensation agents [57]. In comparison to catalytic amidation reactions,
triazine-derived dehydro-condensation agents proceed well also in relatively nonpolar
solvents, which still today limits wide application of catalytic amidation reactions [4].
In fact, in toluene as solvent, CDMT/NMM led to very good yield of 3a (90%) after
1
h, higher than in the presence of DMTMM (entries 13 and 14, Table 1). On the other hand,
significantly lower yields in amide 3a where obtained in water as reaction solvent (entries
15 and 16 of Table 1) probably due to low water solubility of the substrates.
Thus, according to data reported in Table 1, activity and selectivity of CDMT/NMM
system and isolated DMTMM were shown to be very similar. The use of alcohols pro-
moted best performances for both dehydro-condensation systems tested, hence, further
experiments were carried out in CH OH.
3
2.2. Influence of the Tert-Amine on Dehydro-Condensation Reactions
Spurred by the positive results obtained, further dehydro-condensation reactions
for the synthesis of 3a were carried out in the presence of CDMT and different tertiary
N-methyl-substituted aliphatic amines (see Figure 3) employing methanol as solvent. Since,
the synthesis of quaternary ammonium salts prepared from CDMT and N-ethyl tertiary
aliphatic or aromatic amines has been extensively studied in the literature [43], showing
in most cases very unsatisfactory results, N-ethyl tert-amines were not investigated in
this work.
Figure 3. Tert-amines used in combination with CDMT.
Data collected for the synthesis of 3a in the presence of different CDMT/tert-amine
systems were compared, when possible, with corresponding dehydro-condensation data
achieved in the presence of isolated DMT-Ams(X) (see Table 2). In fact, comparison of
the activity of DMT-Ams(X) and CDMT/tert-amine systems as dehydro-condensation
agents was not always possible since, depending on the tert-amine used, the isolation of
the DMT-Ams(X) may be problematic, due to instability of the corresponding quaternary
ammonium salt and formation of a triazine derivative, which is totally inactive as dehydro-
condensation agent (see Scheme 2) [57]. As a matter of fact, only DMTMM was isolated in
good yield while all other DMT-Ams(Cl) were highly unstable and could not be isolated.

Molecules 2021, 26, 191
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Table 2. Dehydro-condensation reaction between 1a and 2a with CDMT/tert-amine system or
isolated 2-(4,6-dimethoxy-1,3,5-triazinyl)trialkyl ammonium salts (DMT-Ams).
Coupling Agent [a]
Counter Anion [b]
Yield (%) [c] (15/60 min)
Entry
−
1
2
3
4
CDMT/NMM
DMTMM
CDMT/NMM
DMTMM
Cl
Cl
93/95
98/99
82/83
38/47
−
−
−
ClO4
ClO4
−
5
6
7
8
CDMT/TMA
Cl
Cl
93/96
n.d.
87/91
79/81
DMTTMA [
d]
−
−
−
CDMT/TMA
DMTTMA
ClO4
ClO4
−
9
CDMT/NMP
Cl
Cl
49/52
n.d.
56/60
86/90
DMTMP [
d]
−
10
11
12
−
−
CDMT/NMP
DMTMP
ClO4
ClO4
−
13
14
15
16
CDMT/MPD
Cl
Cl
65/77
n.d.
68/80
80/85
DMTMPD [
d]
−
−
−
CDMT/MPD
DMTMPD
ClO4
ClO4
−
17
18
19
20
21
22
CDMT/NNDP
Cl
93/96
92/95
79/90
n.d.
77/88
n.d.
CDMT/NNDP [
e]
−
−
−
−
−
Cl
Cl
Cl
[f]
CDMT/NNDP
DMTDP [
d]
CDMT/NNDP
ClO4
ClO4
DMTDP [
d]
◦
Reaction conditions: benzoic acid: 1.3 mmol, phenylethylamine: 1.2 mmol, solvent: CH OH (6 mL), T: 25 C.
3
[a]
Coupling agent: 1.3 mmol of CDMT and 1.3 mmol of tertiary amine were added, for isolated DMT-Ams, 1.3
mmol of were added. [ For the CDMT/tert-amine/NaClO
b]
system, 1.3 mmol of CDMT, 1.3 mmol of NaClO
,
4
4
and 1.3 mmol of tertiary amine were added, while of the isolated system, 1.3 mmol of DMT-Ams(ClO
4
) were
Not
added to the reaction mixture. [ Yield in 3a was measured by GLC using mesitylene as internal standard.
c]
[d]
[e]
[f]
determined since the isolated DMT-Ams(Cl) was not isolated. For this, 0.75 eq of tert-amine used. For this,
.5 eq of tert-amine used.
0
Scheme 2. The 2-(4,6-dimethoxy-1,3,5-triazinyl)trialkyl ammonium salts (DMT-Ams) demethylation.
All CDMT/tert-amine systems tested were active as dehydro-condensation agents,
as reported in Table 2. Similarly to CDMT/NMM, the CDMT/TMA system allowed to
obtain 3a with 96% yield in 1 h (entry 5, Table 2).
Moderately lower yields of amide 3a were obtained with CDMT/NMP (49%, entry 9,
Table 2) or CDMT/MPD (65%, entry 13, Table 2). CDMT was also tested in combination
with 1,4-dimethylpiperazine (NNDP, entries 17–19, Table 2) to verify if double quaternar-
ization of the two tertiary amine functionalities present on NNDP could allow to reduce
the amount of tert-amine required. In fact, when a 1/1 molar ratio of CDMT/NNDP was
employed, yields in 3a achieved were comparable to the ones obtained with DMTMM and
CDMT/NMM (compare entries 1, 2, and 17, Table 2). Notably, when the CDMT/NNDP
molar ratio was decreased to 1/0.75 (entry 18, Table 2) and 1/0.5 (entry 19, Table 2), excel-
lent yields of 3a were still achieved, reducing up to half the amount of tert-amine employed.
−
−
Adversely, DMT-NNDP(X) could not be isolated either with Cl or ClO4 counter an-

Molecules 2021, 26, 191
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ion (see below). From this first screening, higher versatility of CDMT/tert-amine system
compared to isolated DMT-Ams(X) clearly appeared.
In order to compare the activity of CDMT/tert-amine systems with isolated DMT-
Ams(X), stability problems, which strongly limited the library of isolated DMT-Ams(Cl)
−
−
,
available, were partially overcome by counter anion exchange of the Cl atom with ClO4
BF4 , and PF6
−
− − −
[43,55]. Nevertheless, since BF4 and PF6 gave scantly soluble quaternary
ammonium salts, only DMT-Ams(ClO ) were further synthesized and their activity for
4
dehydro-condensation reactions was compared with CDMT/tert-amine systems. Data
reported in Table 2 revealed that most of the isolated DMT-Ams(ClO ) tested for the
4
dehydro-condensation reaction of 1a and 2a gave good yields in 3a, comparable to those
achieved with the corresponding CDMT/tert-amine systems. Nevertheless, it should be
considered that the synthesis of isolated DMT-Ams(ClO ) required the use of organic
4
solvents (THF) and a stochiometric amount of a perchlorate salt, reducing their overall
sustainability.
Moreover, counter anion exchange in the presence of DMTMM strongly reduced
the activity of the corresponding isolated perchlorate salt, and the yield in 3a decreased
from 99% with DMTMM (entry 2, Table 2) to 47% with DMTMM(ClO ), by 1 h (entry 4,
4
Table 2). This behavior may be attributed to two different but correlated phenomena:
substitution of the counter anion generally increased the stability of the isolated ammonium
salt but at the same time, it decreased the solubility of the quaternary ammonium salt
and consequently its reactivity as dehydro-condensation agent [55]. Thus, by counter
anion exchange, DMTMM(ClO ) could be isolated but, in CH OH as solvent, had reduced
4
3
solubility and reactivity as dehydro-condensation agent.
In principle, counter anion exchange should not influence the activity of CDMT/tert-
amine systems, used according to the procedure reported in this work, since no isolation of
DMT-Ams(X) was required and thus stability problems should not be encountered. In fact,
in agreement with this hypothesis and according to data reported in Table 2, the addition
of NaClO in most cases did not significantly alter the activity of the CDMT/tert-amine
4
system. Comparing CDMT/TMA (entries 5 and 7, Table 2), CDMT/NMP (entries 9 and 11,
−
−
Table 2), and CDMT/MPD (entries 13 and 15, Table 2) systems with Cl or ClO anion,
4
yields in 3a were approximately equivalent.
However, for CDMT/NMM/NaClO system, the activity in dehydro-condensation
4
reaction of 1a and 2a significantly decreased and yield of 3a were lower than the ones
achieved with CDMT/NMM, even after 1 h (entries 1 and 3, Table 2).
Since data reported in Tables 1 and 2 showed in most cases very small differences in
yields of 3a after 15 min and 1 h, in order to better compare the reactivity of the CDMT/tert-
amine system to the DMT-Ams(X) one, a kinetic study was carried out (Figure 4). Data
reported in Figure 4 show the kinetic profile for the yield in 3a, monitored by GLC over
a period of 1 h at room temperature, in the presence of CDMT/NMM/ClO system or
4
isolated DMTMM(ClO ) (entries 3–4, Table 2).
4
Notably, formation of 3a was already evidenced after 1 min from the start of the
reaction with both dehydro-condensation systems, and after 5 min significant differ-
ences in the rate of formation of 3a were evident between CDMT/NMM/ClO sys-
4
tem and isolated DMTMM(ClO ). The second considerable gap occurred after 10 min,
4
as the CDMT/NMM/ClO system proceeded with an exponential type trend, while
4
DMTMM(ClO ) maintained an approximately linear trend. Finally, in both cases, a plateau
4
was reached after 15 min.
Data gathered in Table 2 and Figure 4 contributed to give deeper insight into the
activity and versatility of CDMT/tert-amine system compared to isolated DMT-Ams(X) for
carboxylic acid-amine dehydro-condensation reactions, according to the protocol reported
in this work. Counter anion experiments evidenced differences between isolated DMT-
Ams(X) and CDMT/tert-amine systems, possibly ascribable to differences in the reaction
pathway. According to the literature [56,57,62] when isolated DMTMM is employed
as condensation agent, the reaction mechanism initially foresees the reaction between

Molecules 2021, 26, 191
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the carboxylic acid and DMTMM, forming an activated ester (
4), which then undergoes
attack by an amine to give the corresponding amide as illustrated in Scheme 3 pathway a.
Alternatively, literature data report a two steps protocol, foreseeing reaction of CDMT/tert-
amine in the reaction solvent in the presence of a carboxylic acid for approximately 1
h, followed by addition of a primary amine (Scheme 3 pathway b) [43]. According to
literature data, it is generally assumed that, in these reaction conditions, once CDMT and
the tert-amine are added to the reaction solvent, the corresponding quaternary ammonium
salt is formed prior to dehydro-condensation reaction.
Figure 4. Kinetic profile of dehydro-condensation reaction between 1a and 2a in the presence of
CDMT/N-methyl morpholine (NMM)/ClO and DMTMM(ClO ).
4
4
O
N
O
O
N
O
O
a)
O
O
N
N
N
N
OH
+
+
N
H2N
H
N
O
Cl
NMM-HCl
DMTOH
O
1a
2a
3a
DMTMM
4
b)
O
N
O
O
N
O
O
O
O
N
O
2a
NMM
1
a
N
N
N
N
N
N
N
H
N
O
Cl
NMM-HCl
DMTOH
Cl
CDMT
O
3a
DMTMM
4
O
N
O
N
NHCl
O
N
N
OH
DMTOH
O
NMM
NMM-HCl
Scheme 3. Possible known pathways for amidation of 1a and 2a in the presence of 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-
methylmorpholinium chloride (DMTMM) (a) or 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) (
b) /N-methyl morpholine
(
NMM) system.
1
Preliminary experimental evidences collected by H NMR spectroscopy (see Support-
ing Information) seem to indicate that the protocol reported in this work for the use of
CDMT/tert-amine systems differs from previously reported mechanisms and may not lead
to the formation of DMT-Ams(X) as reported in Scheme 3, but possibly to the straight-
forward formation of the intermediate active ester (4), which according to the literature
is supposed to be the rate-determining step, thus boosting the efficacy of the derived

Molecules 2021, 26, 191
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dehydro-condensation agents [58
,
63]. Further experiments are ongoing to gain deeper
insight into this reaction mechanism.
2
.3. CDMT/Tert-Amine Activity for the Dehydro-Condensation of Various Primary Amines and
Carboxylic Acids
To widen the scope of the CDMT/tert-amine system, dehydro-condensation reactions
for the synthesis of different amides were tested (see Figure 5) ranging from aliphatic,
aromatic, sterically hindered, and α,β-unsaturated acids.
DMT-Am
or
O
1
HN R2
R3
CDMT/tert-amine
R -COOH
+
C
R2
CH3OH, r.t.
R1
N
R3
1
5-60 min
1
2
3
1
2
3
R : -Ph
(1a)
(1b)
(1c)
R : -CH CH Ph
R : -H
(2a)
2
2
3
-
-
-
-
CH2Ph
-Ph
R : -H
(2b)
(2c)
(2d)
3
CH2(CH2)5CH3
-CH (CH ) CH
R : -H
2
6
2 2
3
3
CH=CH(CH2)4CH3 (1d)
-C H
R : -H
12
3
CH=CH2
(1e)
-CH CH3
R : -CH CH (2e)
2
2
3
O
O
H
N
N
H
N
H
O
3
a
3b
3c
O
O
O
N
N
N
H
H
H
3
d
3e
3f
O
O
O
N
N
N
H
H
3
g
3i
3
h
Figure 5. Reaction between different acids (1a–e) and different amines (2a–e) in the presence of various CDMT/tert-amine
systems.
Only tert-amines that gave best results, as reported in Table 2, were further investigated
(NMM, NNDP, and TMA). Primary and secondary aliphatic amines as well as aniline could
be condensed to give the corresponding amides (see Table 3). Best yields in 3b were
obtained with CDMT/NMM (87% in 1 h, entry 4, Table 3), although with slightly lower
yield than for 3a (95%, entry 1, Table 3) probably due to reduced nucleophilicity of the
carboxyl group of 1b compared to 1a, which disfavors the formation of the active ester.
Similar charge effects were observed for the synthesis of 3c and 3d (see entries 7 and
10, Table 3). 1e was tested only with CDMT/NMM system giving very low yields (38% in
1
h, entry 13, Table 3).
Further dehydro-condensation reactions of 1a and amines 2b–2e are reported in Table 4.
When amine 2b was used, a specular behavior to the one reported for 3b was observed,
since the presence of a phenyl ring vicinal to the amine functionality increases electron
density on the nitrogen atom reducing the overall dehydro-condensation yield in 3f.

Molecules 2021, 26, 191
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Table 3. Dehydro-condensation reaction of 2a and a carboxylic acid (1a–1e) by CDMT/tert-amine system.
Coupling Agent [a]
Yield (%) [b] (15/60 min)
Entry
Acid
1a
Amide
3a
1
2
3
CDMT/NMM
CDMT/NNDP
CDMT/TMA
93/95
92/95
93/96
4
5
6
CDMT/NMM
CDMT/NNDP
CDMT/TMA
82/87
69/71
45/51
1b
1c
3b
3c
7
8
9
CDMT/NMM
CDMT/NNDP
CDMT/TMA
71/75
65/74
12/15
1
1
1
0
1
2
CDMT/NMM
CDMT/NNDP
CDMT/TMA
88/92
70/86
18/21
1d
1e
3d
3e
1
3
CDMT/NMM
34/38
Reaction conditions: phenethylamine 2a: 1.2 mmol, carboxylic acid (1a
–
3
1e): 1.3 mmol, solvent: CH OH (6 mL), T:
◦
[a]
[b]
25 C. Coupling agent: 1.3 mmol of CDMT and 1.3 mmol of tertiary amine.
Yields were measured by GLC
using mesitylene as internal standard.
Table 4. Dehydro-condensation reaction of 1a and an amine (2b–2e) by CDMT/tert-amine system.
Coupling Agent [a]
Yield (%) [b] (15/60 min)
Entry
Amine
2b
Amide
3f
1
2
3
CDMT/NMM
CDMT/NNDP
CDMT/TMA
58/74
49/65
52/67
4
5
6
CDMT/NMM
CDMT/NNDP
CDMT/TMA
77/93
59/64
72/78
2c
2d
2e
3g
3h
3i
7
8
9
CDMT/NMM
CDMT/NNDP
CDMT/TMA
61/70
55/58
19/30
10
11
12
CDMT/NMM
CDMT/NNDP
CDMT/TMA
56/66
50/55
34/35
◦
Reaction conditions: benzoic acid 1a: 1.3 mmol, amine 2b
Coupling agent: 1.3 mmol of CDMT and 1.3 mmol of tertiary amine.
–
2e: 1.2 mmol, solvent: CH
3
OH (6 mL), T: 25 C.
[a]
[b]
Yields were measured by GLC using
mesitylene as internal standard.
Aliphatic amine 2c gave very good dehydro-condensation yields in 3g, above 75%,
both with CDMT/NMM and CDMT/TMA (entries 4 and 6, Table 4).
Sterical hindrance was supposed to be the cause of moderately lower yields in 3h
.
Secondary aliphatic amines (2e) are known to be less reactive and, in fact, yields in the
corresponding amide (3i) were lower (entries 10–12, Table 4).
3. Materials and Methods
All chemicals were purchased from Sigma Aldrich Co. (St. Louis, MO). GC analyses
were carried out on an Agilent 6850A Gas chromatograph (HP1 capillary column). GC–
MS analyses were performed on an Agilent MS Network 5937 (HP5 capillary column).
1
13
1
Mesitylene was used as internal standard. H and C { H} NMR spectra were recorded on
a Bruker AVANCE 300 spectrometer operating at 300.21 and 75.44 MHz. The chemical shift
values of the spectra are reported in δ units with reference to the residual solvent signal.
Unless otherwise reported, DMT-Ams(ClO ) were synthesized from CDMT with the
4
corresponding tertiary amine and NaOCl according to the synthetic procedure reported
4
in the literature [43,53]. All products, 3a-3i, were characterized and purity was confirmed
by comparison to the literature data [64–70].

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3.1. Synthesis of DMTTMA(ClO4)
TMA (75 mg, 1.27 mmol) was added to a solution of CDMT (200 mg, 1.14 mmol)
◦
and NaClO (155 mg, 1.27 mmol) in THF (4 mL) at 25 C. After stirring for 1 h, the
4
precipitate was collected, washed with THF, and dried under reduced pressure to give
−
◦
1
DMTTMA(ClO4) as a white solid (340 mg, yield 99%). m.p. 163–168 C; H NMR
◦ ◦
300 MHz, D O, 25 C): δ = 4.21 (s, 6H), 3.65 ppm (s, 9H); C NMR (75 MHz, D O, 25 C):
2 2
13
(
−
1
δ = 175.2, 173.6, 58.6, 55.7 ppm; IR (KBr): ve = 1606, 1531, 1485, 1375, 1052, 825, 624 cm
.
3
.2. General Procedure for Dehydro-Condensation Reactions with CDMT/Tert-Amine System
Acid 1a (158.7 mg, 1.3 mmol) was dissolved in a solvent (MeOH, 6 mL) and subse-
quently CDMT (228.2 mg, 1.3 mmol), NMM (131.5 mg, 1.3 mmol), and amine 2a (145.4 mg,
.2 mmol) were added. After 15 min and 1 h, yield in amide 3a was monitored by GLC us-
ing mesitylene as internal standard. To isolate 3a, the reaction mixture was filtered and the
yellowish solid recovered was dissolved in CH Cl and extracted with water (3 30 mL).
1
×
2
2
The combined organic phases were dried over MgSO filtered and concentrated in vacuo
4
to give 3a as a white solid.
3.3. General Procedure for Dehydro-Condensation Reaction with Isolated DMTMM
Acid 1a (158.7 mg, 1.3 mmol) was dissolved in solvent (MeOH, 6 mL) and subsequently
DMTMM (359.7 mg, 1.3 mmol) and amine 2a (145.4 mg, 1.2 mmol) was added. After 15 min
and 1 h, yield in amide 3a was monitored by GLC using mesitylene as internal standard.
The procedure to isolate 3a was the same as abovementioned.
NMR Characterization of Products 3a–3i
1
◦
N-phenylethyl-benzamide (3a): H NMR (300 MHz, CDCl , 25 C): δ = 7.79–7.60 (m,
3
2
H), 7.57–7.08 (m, 8H), 6.10 (bs, 1H), 3.73 (q, J = 6.6 Hz, 2H), 2.95 ppm (t, J = 6.9 Hz, 2H);
1
3
◦
C NMR (75 MHz, CDCl , 25 C):
δ
= 167.4, 138.4, 134.5, 132.0, 128.8, 128.6, 127.7, 126.5,
3
1
25.9, 41.1, 34.9 ppm.
1
◦
(3b): H NMR (300 MHz, CDCl , 25 C): δ = 7.35–
3
N-phenethyl-2-phenylacetamide
.28 (m, 2H), 7.28–7.21 (m, 1H), 7.21–7.17 (m, 1H), 7.06–7.02 (m, 1H),5.52 (bs, 1H), 3.54 (s,
7
2
H), 3.47 (c, J = 6.7 Hz, 2H), 2.75 ppm (t, J = 6.7 Hz, 2H); 13C NMR (75 MHz, CDCl , 25 C):
◦
3
δ = 171.2, 138.9, 135.1, 129.6, 129.2, 128.2,128.2, 127.1, 126.4, 43.8, 40.9, 35.6 ppm.
1
◦
N-Phenethyloctanamide (3c) H NMR (300 MHz, CDCl , 25 C): δ = 7.30 (t, J = 7.3 Hz,
3
2
2
0
H), 7.25–7.21 (m, 1H), 7.21–7.14 (m, 2H), 5.57 (br. s, 1H), 3.51 (q, J = 6.8 Hz, 2H),
.81 (t, J = 6.8 Hz, 2H), 2.11 (t, J = 7.6 Hz, 2H), 1.62–1.53 (m, 2H), 1.31–1.20 (m, 8H),
.87 ppm (t, J = 6.7 Hz, 3H); 13C NMR (75 MHz, CDCl , 25 C):
◦
δ
= 173.3, 139.1, 128.9, 128.7,
3
1
26.6, 40.6, 36.9, 35.8, 31.8, 29.3, 29.1, 25.9, 22.7, 14.2 ppm.
1
◦
N-(2-phenylethyl)oct-2-enamide
(
3d) H NMR (300 MHz, CDCl , 25 C):
δ
= 7.30
3
(
t, J = 7.3 Hz, 2H), 7.25–7.21 (m, 1H), 7.21–7.14 (m, 2H), 5.57 (br. s, 1H), 3.51 (q, J = 6.8 Hz,
2
0
H), 2.81 (t, J = 6.8 Hz, 2H), 2.11 (t, J = 7.6 Hz, 2H), 1.62–1.53 (m, 2H), 1.31–1.20 (m, 8H),
.87 ppm (t, J = 6.7 Hz, 3H); 13C NMR (75 MHz, CDCl , 25 C):
◦
δ
= 173.3, 139.1, 128.9, 128.7,
3
1
26.6, 40.6, 36.9, 35.8, 31.8, 29.3, 29.1, 25.9, 22.7, 14.2 ppm.
1
◦
2-phenylethyl acrylamide
(
3e) H NMR (300 MHz, CDCl , 25 C):
δ
= 7.27–7.20 (m,
3
5
2
H), 6.92–6.87 (m, 1H), 6.18–6.12 (m, 1H), 3.44(t, J = 5.1 Hz, 2H), 2.72 (t, J = 5 Hz, 2H),
13
.22–2.18 (q, J = 6.8 Hz, 2H), 1.38–1.25 (m, 6H). 0.90 ppm (m, 3H); C NMR (75 MHz,
◦
CDCl , 25 C):
δ = 166.8, 142.1, 138.8, 128.7, 128.6, 125.4,122.1, 40.6, 35.6, 33.8, 32.9, 31.8,
3
2
8.5, 22.7, 14.3 ppm.
Phenylbenzamide
C NMR (75 MHz, CDCl , 25 C):
1
◦
(
3f) H NMR (300 MHz, CDCl , 25 C):
δ
= 7.13–7.87 ppm (m, 10H);
3
13
◦
δ
= 165.8. 138.0 135.0 131.9, 129.1, 128.8, 127.1, 124.6,
3
1
20.3 ppm.
1
◦
N-Butylbenzamide
(
3g) H NMR (300 MHz, CDCl , 25 C):
δ
= 7.74–7.78 (m, 2H),
3
7
.47–7.51 (m, 1H), 7.40–7.45 (m, 2H), 6.14 (br s, 1H), 3.46 (dt, 2H, J = 6.8, 6.4 Hz), 1.61 (tt, 2H,
13
J = 7.2, 7.2 Hz), 1.42 (qt, 2H, J = 7.2, 7.6 Hz), 0.96 ppm (t, 3H, J = 7.4 Hz); C NMR (75 MHz,
CDCl , 25 C): δ = 167.6, 134.9, 131.3, 128.5, 126.8, 39.8, 31.8, 20.2, 13.8 ppm.
◦
3

Molecules 2021, 26, 191
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1
◦
N-Hexylbenzamide
(
3h) H NMR (300 MHz, CDCl , 25 C):
δ
= 7.77–7.75 (m, 2H),
3
7
.39–7.47 (m, 3H), 6.42 (br s, 1H, NH), 3.43 (d, J = 5.5 Hz, 2H), 1.60 (d, J = 6.5 Hz, 2H),
13
1.36 (s, 2H), 1.31(d, J = 2.5 Hz, 4H), 0.88 ppm (d, J = 6.0 Hz, 3H); C NMR (75 MHz, CDCl3,
◦
25 C): δ = 167.5, 134.8, 131.2, 128.4, 126.8, 40.1, 31.5, 29.6, 26.6, 22.5, 14.0 ppm.
1
◦
N,N-Diethylbenzamide
(
3i). H NMR (300 MHz, CDCl , 25 C):
δ
= 7.46
−
7.30 (m,
3
13
◦
5
H), 3.40 (br s, 4H), 1.17 ppm (br s, 6H); C NMR (75 MHz, CDCl , 25 C):
δ
= 171.3, 137.3,
3
129.1, 128.4, 126.3, 43.2, 39.2, 14.1, 12.9 ppm.
4. Conclusions
In summary, a library of CDMT/tert-amine systems was investigated and their ac-
tivity as dehydro-condensation agents for the production of amides compared to similar
isolated quaternary ammonium salts synthesized by reaction of CDMT with a tert-amine
− −
(
DMT-Ams(X), with X: Cl or ClO4 ) was studies. In most cases, the CDMT/tert-amine
systems prepared by simultaneous addition of a carboxylic acid, an amine, CDMT, and a
tert-amine in the reaction solvent gave comparable or higher yields than the corresponding
−
−
isolated DMT-Ams(X) species, both with Cl or ClO4 as counter anion. In the pres-
−
ence of Cl as counter anion, only DMTMM could be synthesized and employed for
dehydro-condensation reaction of 1a and 2a, while all corresponding CDMT/tert-amine
system tested gave high yields in amide 3a. Further studies are ongoing to gain deeper
insight into the possible mechanistic differences between the two families of dehydro-
condensation agents.
Moreover, CDMT/tert-amine may be used in alcohols or even water without any
influence on the selectivity in the desired amide, adversely to other amidation protocols,
which require less environmentally friendly and more expensive aprotic solvents.
The possibility to use CDMT/tert-amine systems allowed to achieve a library of easy
and sustainable dehydro-condensation agents. Consequently, tert-amines could be chosen
according to specific requirements such as availability, cost and risk assessment, and fea-
tures, which may be crucial for industrial applications [71]. Additionally, amines such as
NNDP, having two reactive tert-amine groups, allowed to reduce the consumption of the
tert-amine up to 50%. Further advantage of both CDMT/tert-amine systems and DMTMM,
compared to other dehydro-condensation agents commonly used today, is that triazine
by-product formed during the reaction (DMTOH) is nontoxic and can be recovered and
recycled to produce CDMT or DMTMM [26]. In summary, CDMT/tert-amine systems, for-
mulated according to the specific protocol reported in this work, have been demonstrated
to be very active, versatile, simple, and environmentally sustainable alternatives to many
conventional dehydro-condensation agents employed today.
Supplementary Materials: The Supplementary Materials are available online, Chapter I contains the
1
NMR and FT-IR spectra of DMTTMA(ClO ) and Chapter II contains the H NMR of the dehydro-
4
condensation reaction products and triazine derivatives monitored in time.
Author Contributions: All authors: conceptualization, methodology, writing—review and editing;
V.B., R.S., and V.G.: data analysis; V.B., R.S., V.G., S.C., N.B. and A.M.: writing—original draft.
All authors have read and agreed to the published version of the manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: Not applicable.
Conflicts of Interest: The authors declare no conflict of interest.
Sample Availability: Samples of the compounds are available from the authors.

Molecules 2021, 26, 191
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