Paper
To probe the reaction mechanism, several preliminary
RSC Advances
Notes and references
experiments were conducted (Scheme 3). Under standard reac-
tion conditions, methyl 2-aminobenzoates 7 reacted with 2a to
provide compound 8 in 92% yield, and 4a was not detected. This
control experiment indicated the importance of hexa-
uoroisopropyl (Scheme 3, eqn (1)). Treatment of methyl 2-
aminobenzoates 7 with 5a in the presence of K3PO4 did not
furnish any product 6a, and 3a did not convert at all (Scheme 3,
eqn (2)). On the basis of the control experiments and previous
reports, we propose a possible mechanism. First, aza-oxyallyl
cation A is formed from a-bromoamide with Cs2CO3.15 Where-
aer, aza-oxyallyl cation A combines with 1a to produce
compound 3a.15b The product 4a is obtained via intramolecular
´
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methods, the transformations of the obtained 1,4-benzodiaze-
pines and quinazolinones were performed (Scheme 4).
Compound 9 was formed from 4a through cleavage of the N–O
bond with Mo(CO)6 (Scheme 4, eqn (1)). The quinazolinones
can be transformed into substituted quinazolines with anilines
or phenols as nucleophilic reagents in the presence of BOP and
DBU (Scheme 4, eqn (2) and (3)).
We next investigated the cytotoxicity of the products and
their derivatives against cancer cell lines (A549, HCT116 and
MCF7) by MTT assay, with 5-uorouracil (5-FU) as the positive
control. To our delight, some products and their derivatives
exhibited potent inhibitory activities, and some of them showed
better inhibitory activities than 5-Fu (Table 4). These results
revealed that our methods had potential applications in
discovering new lead compounds with anti-tumor activities.
In summary, we have developed novel and simple
approaches for the synthesis of 1,4-benzodiazepines and qui-
nazolinones from hexauoroisopropyl 2-aminobenzoates with
a-bromoamides or amidines hydrochloride. These protocols
feature readily available starting materials, mild reaction
conditions, good functional group tolerance, and excellent
yields. In addition, the newly obtained products and their
derivatives showed potent anticancer activities in vitro by MTT
assay. Further studies on the synthesis of other N-heterocycles
from hexauoroisopropyl 2-aminobenzoates are in progress.
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Conflicts of interest
There are no conicts to declare.
Acknowledgements
´
M. K. Rogacki, J. Gomez, F. Cunningham, J. Joosens,
This work was supported by the National Natural Science
Foundation of China (21702096), and the High-level Talent
Introduction Foundation of Southern Medical University
(C1033520) for nancial support.
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© 2021 The Author(s). Published by the Royal Society of Chemistry
RSC Adv., 2021, 11, 4966–4970 | 4969