TCT-mediated synthesis of N-acylbenzotriazoles in aqueous media

Article abstract of DOI:10.1016/j.tetlet.2015.10.109

The synthesis of N-acylbenzotriazoles has been demonstrated by the 2,4,6-trichloro-1,3,5-triazine (TCT)-mediated condensation of carboxylic acids with 1H-benzotriazole in aqueous media. In saturated aqueous sodium bicarbonate, TCT was found to be relatively stable and functioned as an efficient acid activator in the acyl transfer process. This operationally simple and economic method allows the scalable synthesis of N-acylbenzotriazoles in good to excellent yields.

Full text of DOI:10.1016/j.tetlet.2015.10.109

Accepted Manuscript
TCT-mediated synthesis of N-acylbenzotriazoles in aqueous media
Sirawit Wet-osot, Wong Phakhodee, Mookda Pattarawarapan
PII:
S0040-4039(15)30306-3
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.10.109
TETL 46938
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
13 August 2015
27 October 2015
29 October 2015
Please cite this article as: Wet-osot, S., Phakhodee, W., Pattarawarapan, M., TCT-mediated synthesis of N-
acylbenzotriazoles in aqueous media, Tetrahedron Letters (2015), doi: http://dx.doi.org/10.1016/j.tetlet.
2015.10.109
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TCT-mediated synthesis of N-acylbenzotriazoles in aqueous media
Sirawit Wet-osot, Wong Phakhodee, and Mookda Pattarawarapan*
Department of Chemistry and Center of Excellence for Innovation in Chemistry, Faculty of
Science, Chiang Mai University, Chiang Mai 50200, Thailand
Abstract
The synthesis of N-acylbenzotriazoles has been demonstrated by the 2,4,6-trichloro-
1,3,5-triazine (TCT)-mediated condensation of carboxylic acids with 1H-benzotriazole in
aqueous media. In saturated aqueous sodium bicarbonate, TCT was found to be relatively stable
and functioned as an efficient acid activator in the acyl transfer process. This operationally
simple and economic method allows the scalable synthesis of N-acylbenzotriazoles in good to
excellent yields.
Keywords cyanuric chloride; aqueous; N-acylbenzotriazoles; carboxylic acids

Introduction
In the recent years, considerable attention has been directed toward the use of water as a
media in organic synthesis due to it being inexpensive, readily available, nontoxic, and non-
inflammable.1 Additionally, the ability to a form hydrogen bonding network, high surface
tension, high heat capacity, and large dielectric constant have often been shown to enhance
reactions rate and selectivity.2 Thus, the development of new aqueous-mediated processes are of
great benefit in terms of safety, handling simplicity, as well as reaction outcomes that may not be
readily achieved with organic solvents.
N-Acylbenzotriazoles are neutral acylating agents which have been applied as acid
chloride replacements in a number of organic transformations, including the synthesis of
diketones,3 amides or peptides,4 oxazolines,5 and thiazoline.5 Unlike acid chlorides which are
unstable or difficult to isolate, N-acylbenzotriazoles are stable solids that can be kept at room
temperature without decomposition.6 Acylation reactions using these benzotriazole derivatives
have also been shown to give high yields and high regiospecificity without racemization.
Despite their distinct synthetic advantages, methods aimed toward the synthesis of N-
acylbenzotriazoles are rather limited. The classical procedure involves treatment of acid
chlorides with 1H-benzotriazole (BtH) or its derivatives.6c However, an additional step is needed
for the formation of the requisite acid chlorides. A more convenient and straightforward method
is via the in situ generation of the activated acid-derivative for the reaction with BtH. Different
systems such as SOCl2 with excess BtH,6 PPh3/I2,7 and 2,4,6-trichloro-1,3,5-triazine (TCT)/Et3N8
have been shown to effectively convert various carboxylic acids into their benzotriazole
derivatives. Nevertheless, these reactions were carried out in harmful organic solvents which
require drying of solvents and/or reactants prior use.
Among the known acid activating systems for the preparation of amides,9 TCT is
considered highly attractive in terms of its low cost, stability, and availability.10 This reagent is
generally employed in organic solvents in the presence of organic tertiary amine bases.11 To the
best of our knowledge, TCT mediated acid activation in water has only been described in one
study that reported the use of TCT in 4:1 acetonitrile-water.11d In a continuation of our interest in
reactions promoted by TCT, herein, we report the TCT-mediated condensation of carboxylic

acids with BtH in aqueous media as a facile and economic procedure for the preparation of N-
acylbenzotriazoles (Scheme 1).
Scheme 1. TCT-mediated condensation of carboxylic acids with BtH in aqueous media.
Results and discussion
To successfully perform the condensation reaction in water, there are various factors that
must be considered. Firstly, the reactants need to be soluble in the reaction media, while TCT
should selectively react with the carboxyl group rather than with water, to give an activated acid-
derivative in the first activation step. Secondly, in the acyl transfer process, the activated acid
must be preferentially react with BtH in order to give the desired N-acylbenzotriazole faster than
its solvolysis. Finally, the formed N-acylbenzotriazole should be stable enough to survive the
aqueous conditions.
Based on previous studies,4h-4j N-acylbenzotriazoles have occasionally been used in
aqueous reactions and thus should not undergo hydrolysis under weakly basic conditions such as
in saturated sodium bicarbonate. Although TCT has a tendency to react with water, at low
o
temperature (ca. 0 C), TCT is known to be stable for at least 12 h without detectable
decomposition.12 Considering the solubility of all the reactants, both BtH and carboxylic acids
are soluble in aqueous basic media. However, TCT exhibits low solubility and thus requires the
addition of a small amount of acetone, as well as a surfactant, to facilitate its reaction in water.
In our initial investigation, the condensation between benzoic acid and BtH was carried
out by adding a solution of TCT in acetone (0.54 mmol in 1 mL) to a saturated aqueous NaHCO3
o
solution of the acid (0.54 mmol in 5 mL). The mixture was stirred at 0 C for 30 min before
o
treatment with BtH (0.59 mmol), followed by stirring at 25 C for 20 min. Without any
surfactant, the reaction resulted in low product yield (44%).

We then screened for a suitable additive using various surfactants including neutral
(Triton X100), anionic (SDS), and cationic (tricaprylylmethylammonium chloride) derivatives,
as well as phase transfer catalysts. Using 10 mol% of a surfactant (the concentration higher than
their critical micelle concentrations in water),13 the reaction conducted in the presence of Triton
X100 gave no conversion, while SDS yielded only 34% of the product, possibly due to excessive
bubble formation. Using 10 mol% of tricaprylylmethylammonium chloride gave no bubbles and
the product yield was increased to 66%. However, excellent yields (93% and 91%, respectively)
were obtained from reactions catalyzed by tetrabutylammonium bromide (TBAB) and
tetrabutylammonium chloride (TBAC), respectively, while tetrabutylammonium iodide (TBAI)
gave a slightly lower yield (87%). The TBAB-catalyzed reaction was then carried out using 0.66
equiv of TCT per mole of acid which provided the product in a comparative yield (92%).
Additionally, decreasing the amount of TCT to 0.33 equiv. gave lower conversion (65%),
possibly due to partial hydrolysis of the reagent.
We next investigated the applicability of the method using 0.66 equiv. of TCT and
catalytic TBAB using a range of carboxylic acids including aromatic, aliphatic, and ,-
unsaturated acids.14 As shown in Table 1, benzoic acid and its derivatives bearing electron-
donating or withdrawing substituents reacted rapidly within 15-30 min to give the desired
products in good to excellent yields (entries 1-10). The presence of a substituent at the ortho
position lowered the product yields, possibly due to steric hindrance (entries 2, 5, 8). Notably,
substrates containing secondary amines were well tolerated under the weakly basic conditions
(entries 7,8). Even carboxylic acids with low aqueous solubility such as 1-naphthoic acid and
cinnamic acid (entries 11,12), gave the corresponding BtH derivatives in good yields with no
Michael addition side reaction or double bond isomerization being observed in the latter case
(entry 12). Aliphatic acids containing up to a six-carbon chain were also found to react smoothly
(entries 13-18).
To demonstrate the practicality of the developed method, the benzotriazole derivative of
benzoic acid was prepared on a multi-gram scale. In the scale-up reaction, it was found that the
amidation of 20 mmol of benzoic acid could be carried out using 0.66 equiv of TCT per mole of
acid and after 30 min activation time and 30 min reaction time with BtH, N-benzoylbenzotriazole

was obtained in 88% yield after extraction with dichloromethane, followed by passing through a
short pad of silica.
Table 1. Preparation of N-acylbenzotriazoles in
aqueous mediaa
entry
1
R
time (min) yield (%)
C6H5
15
30
30
15
30
15
15
15
15
30
15
15
15
15
15
30
15
15
9415
657
2
2-CH3C6H4
3
3-CH3C6H4
897
4
4-CH3C6H4
8715
6816
8517
70
5
2-CH3OC6H4
4-CH3OC6H4
3-(CH3)2NC6H4
2-PhNHC6H4
4-ClC6H4
6
7
8
59
9
8716
8116
8516
9018
8919
7320
89
10
11
12
13
14
15
16
17
18
4-NO2C6H4
1-naphthyl
cinnamyl
1-napthylacetyl
2-(2-methoxyphenyl)acetyl
2-(2,6-dichlorophenyl)acetyl
5-phenylvaleryl
pentanoyl
927
8416
9021
hexanoyl
aReaction conditions: To a sat. aqueous NaHCO3 (5 mL) containing
the carboxylic acid (0.54 mmol) was added TBAB (0.054 mmol)
then TCT (0.54 mmol) in acetone (1 mL) and stirred for 30 min at 0
oC. BtH (0.59 mmol) was added and stirred at 25 oC for the specified
time.
It is important to note that unlike the previous reports on the TCT-mediated carboxylic
acid activation where TCT was used with a tertiary amine base and volatile organic solvent,11, 12

this work has demonstrated that TCT could also be effectively applied to reactions in aqueous
media using an inexpensive inorganic base. Moreover, since the residual hydroxyl derivatives of
TCT and the remaining reactants are all soluble in aqueous base, a simple solvent extraction and
1
filtration was sufficient to provide N-acylbenzotriazoles in high purity based on H-NMR
spectroscopic analysis of the isolated products.
In summary, a practical TCT-mediated condensation of carboxylic acids with BtH in
aqueous media was reported. The protocol enabled a range of N-acylbenzotriazoles to be
synthesized under mild and relatively neutral conditions using inexpensive and easy to handle
reagents. The operational simplicity, high product yields, and scalability of the method will be of
great benefit and could potentially lead to the development of more economic synthesis of other
important carboxylic acid derivatives from water soluble nucleophiles.
.
Acknowledgements
The Center of Excellence for Innovation in Chemistry (PERCH-CIC), the Graduate School,
Chiang Mai University, and the National Research University Project under Thailand’s Office of
the Higher Education Commission are gratefully acknowledged for financial support of this
research.
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132.5, 132.1, 130.2, 129.0, 126.2, 120.1, 119.7, 117.5, 114.8, 40.5; HRMS (ESI-TOF) m/z calcd for C15H15N4O [M + H]+
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= 8.4, 0.8 Hz, 1H), 7.68 (t, J = 7.6 Hz, 1H), 7.53 (t, J = 7.6 Hz, 1H), 7.43 (t, J = 7.6 Hz, 1H), 7.38-7.34 (m, 3H), 7.28 (d, J
= 7.6 Hz, 2H), 7.11 (t, J = 7.6 Hz, 1H), 6.89 (t, J = 7.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 167.5, 148.9, 145.8,
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+
H]+ 315.1246, found 315.1249. 1-(1H-Benzo[d][1,2,3]triazol-1-yl)-2-(2,6-
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8.0 Hz, 2H), 7.26 (t , J = 8.0 Hz, 1H), 5.17 (s, 2H); 13C NMR (100 MHz, CDCl3) δ 168.0, 146.2, 136.4, 130.6, 130.0,
129.6, 128.2, 126.3, 120.3, 114.4, 38.2; HRMS (ESI-TOF) m/z calcd for C14H10Cl2N3O [M + H]+ 306.0201, found
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Graphical Abstract
Leave this area blank for abstract info.
TCT-mediated synthesis of N-
acylbenzotriazoles in aqueous media
Sirawit Wet-osot, Wong Phakhodee, and Mookda Pattarawarapan*