Received: September 17, 2013 | Accepted: November 5, 2013 | Web Released: April 5, 2014
CL-130839
Task-specific Ionic Liquid-mediated Facile Synthesis of 1,3,5-Triaryltriazines
by Cyclotrimerization of Imines and Their Biological Evaluation
Anshu Dandia,* Anuj K. Jain, and Sonam Sharma
Center for Advance Studies, Department of Chemistry, University of Rajasthan, Jaipur-302004, India
(E-mail: dandia-anshu@uniraj.ernet.in)
A highly efficient method for the synthesis of fluorinated
1,3,5-triaryltriazine derivatives is developed by the condensation
reaction of aromatic amines and formaldehyde followed by
spontaneous cyclotrimerization using task-specific 1,1,3,3-tetra-
methylguanidine trifluoroacetate [TMG][Tfa] ionic liquid as a
environmentally benign solvent in excellent yields at room
temperature. The synthesized compounds were subjected for
in vitro antitubercular activity against Mycobacterium tuber-
culosis H37Rv strain using the Löwenstein-Jensen medium.
A number of synthetic methods to prepare these compounds
have been described in the past few years.20 All of these methods
have certain limitations such as tedious procedures, long
reaction time, harsh reaction conditions, low yields, high boiling
solvents, or microwave activation. Therefore, further studies are
still necessary for the versatile, simple, and eco-friendly process.
In recent years, the development of efficient and environ-
mentally benign chemical process or methodologies for widely
used recycle catalyst and eco-friendly solvent is one of the major
challenges for chemists in organic synthesis. Ionic liquids (ILs)
have received recognition as a new generation of solvents
having unique physicochemical properties, such as nonvolatility,
excellent chemical and thermal stability, nonflammability, and
good solvating ability. Their dual organic and ionic nature
allows them to establish ion-ion and ion-dipole as well as
van der Waals interactions with reacting species, including
transition states; hence they sometimes give rise to improved
yields and rate enhancements. Over the past few years, a number
of reactions have been successfully conducted using ionic
liquids as solvents or catalysts.21 In the search of developing
simple, mild, and environmentally friendly synthetic protocols,
we have recently developed highly efficient synthetic method-
ology for the construction of pharmaceutically important spiro
heterocycles using green chemistry technique.22
Tuberculosis is a communicable disease which is caused by
Mycobacterium tuberculosis. The global effect of tuberculosis
is immense.1 According to the World Health Organization,
currently one-third of world’s population is infected with latent
tuberculosis.2 In recent years, the 15 emergence of multidrug-
resistant tuberculosis (MDR-TB) and extensively drug resistant
tuberculosis (XDR-TB) strains have susceptible global control
of TB. MDR-TB strains are defined as being resistant to the first-
line antitubercular agent isoniazid which highlights the need for
advance development of new antimycobacterial drugs.3
The increased interest in organofluorine compounds have
led to the development of novel medicinal agents and new
strategies in drug discovery and development. The synthesis of
fluorine-containing complexes or compounds and their deriva-
tives provide unlimited potential for creating novel pharmaco-
logically active lead compounds for use as therapeutics.4,5 The
installation of fluorine atoms in an organic molecule changes the
molecule’s physicochemical properties, including its stability,
bioavailability, and lipophilicity.6,7
The small atomic radius, high electronegativity, and low
polarizability of the carbon-fluorine bond are among the special
properties that make fluorine so attractive. Thus many fluori-
nated compounds are stable and frequently avoid undesirable
metabolic transformations.8 In addition, the increased lipophi-
licity often leads to easy absorption and transportation of
molecules within biological membranes, thereby improving their
overall pharmacokinetic and pharmacodynamic properties.9
However, prediction of sites in a molecule at which fluorine
substitution will result in optimal desired effects is still
challenging. Therefore, the synthesis of organofluorine com-
pounds provides a diverse array of building blocks and chemical
substructures for novel processes.10,11
1,3,5-Trisubstituted hexahydro-1,3,5-triazines have been
emerged as an important target molecules for chemist due
to their therapeutic and pharmacological properties such as
antimicrobial,12 anticancer,13 antimalerial,14 antitubercular,15
antioxidant,16 and anti-HIV agents.17 They have also been used
for protection of amino group as well as for the synthesis of
polyamines.18 They serve as valuable precursors for the synthe-
sis of α- and β-amino esters, β-lactams, and natural alkaloids.19
In continuation of our ongoing program in the development
of greener and sustainable process for medicinally important
heterocycles22 and our expertise in ionic liquids23 and fluorine
chemistry,24 herein, we wish to report for the first time, a highly
efficient and green protocol for the synthesis of highly
substituted triazines incorporating pharmacophoric fluorine or
trifluoromethyl group using task-specific [TMG][Tfa] ionic
liquid as the recyclable solvent.
To approach the synthesis, we first focused our studies on
the model reaction (Scheme 1), involving 4-fluoroaniline (1c)
and formaldehyde (2), with the expected production of the
desired triazine derivatives. In this regard, we attempted to
determine the optimum conditions by examining the influence of
ILs, on the progress of the trial reactions (Table 1). It can be seen
F
F
NH2
H
H
N
N
Ionic liquid
r.t., stirring
O
+
N
F
3c
2
F
1c
Scheme 1. Model reaction for exploring the use of room-
temperature ionic liquids (RTILs) for the synthesis of 1,3,5-
tris(4-fluorophenyl)-hexahydro-1,3,5-triazine (3c).
© 2014 The Chemical Society of Japan | 521
Dandia, Anshu
