S. Wet-osot et al.
observed, possibly due to steric hindrance of the –OMe
group at the ortho position. Although halogen substituents
on the aromatic ring did not significantly affect the reaction
times and yields (entries 6–9), the strong electron-with-
drawing NO2 group dramatically reduced the product
yields, especially when it was present at the para position
(entries 10, 11).
layer chromatography was carried out on silica gel plates
(60F254, MERCK, Germany) and visualized under UV light
(245 nm). Melting points were determined using SANYO,
Gallenkamp apparatus at a heating rate of 10 °C/min. NMR
measurements were conducted on a Bruker AVANCETM
1
(400 MHz for H) using tetramethylsilane (TMS) as an
internal standard. Chemical shifts were reported in parts
per million (d/ppm) downfield from TMS. Splitting pat-
terns are described as singlet (s), doublet (d), triplet (t),
multiplet (m), doublet of doublet (dd), and triplet of dou-
blet (td). High resolution mass spectrometry (HRMS) was
performed with a MicroTOFLC (Bruker Daltonics).
The reaction with relatively steric hindered 1- and
2-naphthoic acids as well as a,b-unsaturated cinnamic acid
(entries 12–14) proceeded smoothly without any side
reactions. However, aliphatic acids including hexanoic
acid, octanoic acid, and 5-phenylvaleric acid (entries
15–17) were less reactive compared with aromatic acids
and both the acid activation and the reaction times needed
to be prolong to give the corresponding N-acylbenzotria-
zoles in good to high yields.
General procedure for synthesis
of N-acylbenzotriazoles
To demonstrate the practical utility of the established
method, the reaction of 4-chlorobenzoic acid with BtH was
performed in a larger scale using 10 mmol of the acid.
Upon 5 min activation of TCT with Et3N and 15 min
reaction time with BtH, the expected product was obtained
To a solution of 0.024 g TCT (0.130 mmol) in 2 cm3
CH2Cl2 was added 0.033 g triethylamine (0.325 mmol) at
0 °C and the resulting mixture was stirred for 5 min.
Carboxylic acid (0.271 mmol) was then added with con-
tinuously stirring for 10 min. Subsequently, to this mixture
was added 0.032 g 1H-benzotriazole (0.271 mmol) and the
solution was allowed to warm up to room temperature and
stirred until completion of the reaction based on TLC
analysis. The crude reaction mixture was extracted with
saturated NaHCO3, then washed with 1 M HCl and water.
The combined organic layer was dried over anhydrous
sodium sulfate and concentrated under reduced pressure to
afford the product. All known products were characterized
1
in quantitative yield with high purity (based on H NMR)
after simple aqueous work up without column
chromatography.
It is important to note that although there have been
some reports on the formation of acid chlorides using a
combination of TCT with tertiary amine bases [30–32], in
our study, we did not observe formation of acid chlorides
after acid activation at low temperature based on TLC
which was in accordance with other studies using TCT in
amide bond formation [33–36]. Nevertheless, attempts to
isolate the formed intermediate led to rapid decomposition
due to its high reactivity [20]. Thus, at this point, we can
only assume that triacyloxy-1,3,5-triazine was being gen-
erated before reacting with BtH.
1
by H and 13C NMR and their spectroscopic data were
consistent with those reported in literature.
Acknowledgments The Center of Excellence for Innovation in
Chemistry (PERCH-CIC), and the National Research University
Project under Thailand’s Office of the Higher Education Commission
are gratefully acknowledged for financial support.
Conclusion
References
In conclusion, a facile, efficient, and economic protocol for
the direct conversion of carboxylic acids into N-acylben-
zotriazoles was developed using TCT-Et3N as the
promoter. The reaction was not only very rapid, but also
used less than a stoichiometric amount of TCT, which
minimizes the reagent utilization and waste generation. In
addition, the ease of product isolation makes this method
viable for the synthesis of N-acylbenzotriazoles.
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All reagents were purchased from Sigma-Aldrich Co.,
USA, and were used without further purification. Thin-
123