An ionic liquid mediated Friedel-Crafts addition of arenes to isothiocyanates

Article abstract of DOI:10.1139/v03-152

A new protocol is developed for the synthesis of N-substituted thioamides, employing arenes and isothiocyanates in 1-butyl-3-methylimidazolium chloroaluminate ionic liquid, [bmim]Cl·2AlCl₃, as a homogenous Lewis acid catalyst and solvent. The e

Full text of DOI:10.1139/v03-152

1057
COMMUNICATION / COMMUNICATION
An ionic liquid mediated Friedel–Crafts addition of
arenes to isothiocyanates
Prashant U. Naik, Susheel J. Nara, Jitendra R. Harjani, and
Manikrao M. Salunkhe
Abstract: A new protocol is developed for the synthesis of N-substituted thioamides, employing arenes and isothio-
cyanates in 1-butyl-3-methylimidazolium chloroaluminate ionic liquid, [bmim]Cl·2AlCl3, as a homogenous Lewis acid
catalyst and solvent. The effect of Lewis acidity and the stoichiometry of the ionic liquid on the extent of product for-
mation is studied. Studies reveal that a progressive increase in yields was observed with increasing Lewis acidity, and
two equivalents of [bmim]Cl·2AlCl3 was the optimal amount for the reaction. A distinct para selectivity for the incom-
ing thioamido group on activated arenes was observed under ambient conditions.
Key words: arenes, isothiocyanates, Friedel–Crafts, ionic liquids, thioamides.
Résumé : On a développé un nouveau protocole pour la synthèse de thioamides N-substitués qui fait appel à l’utilisa-
tion d’arènes et d’isothiocyanates dans du chloroaluminate de 1-butyl-3-méthylimidazolium, [bmim]Cl·2AlCl3, un li-
quide ionique qui agit comme catalyseur acide de Lewis homogène et comme solvant. On a étudié l’effet de l’acidité
de Lewis et la stoechiométrie du liquide ionique sur le niveau de formation du produit. Les études révèlent qu’une aug-
mentation progressive des rendements peut être observée avec une augmentation de l’acidité de Lewis et que deux
équivalents de [bmim]Cl·2AlCl3 correspond à la quantité optimale pour la réaction. Dans les conditions ambiantes, on a
observé une sélectivité para pour le groupe thioamido qui s’insère sur les arènes activés.
Mots clés : arènes, isothiocyanates, Friedel–Crafts, liquides ioniques, thioamides.
[Traduit par la Rédaction] Naik et al. 1060
Introduction
derivatives as useful building blocks in organic syntheses
has been recently reviewed (9). Thioamides are a class of
compounds that comprise a variety of derivatives that pos-
sess diverse physiological properties such as antigastric,
antiulcer, antidiabetic, antitubercular, fungistatic, etc. (10).
Besides, they have been technically applied in a number of
commercial applications as vulcanisation promoters, antioxi-
dants, corrosion inhibitors, etc. (10). Activated arenes are
known to undergo Lewis acid mediated amidation (11, 12)
and thioamidation (13, 14) with isocyanates and isothiocy-
anates, respectively. In contrast to the Lewis acid mediated
amidation of arenes with isocyanates, thioamidation with
isothiocyanates has been particularly attractive, as the for-
mer procedure often suffers from the disadvantage of low
yields of products. The isothiocyanato group is one of the
excellent acceptors of nucleophiles, and its reactivity has
been aptly utilized in various synthetic procedures (15).
With Lewis acids, the isothiocyanato group is known to
Room temperature ionic liquids have attracted consider-
able attention as novel reaction media, offering cleaner and
environmentally benign protocols to a number of chemical
processes (1). An appropriate amalgamation of properties
possessed by these liquids, such as high thermal stability, re-
usability, nonvolatility, and excellent solvating ability has
undoubtedly made them the most protean and promising sol-
vents of the future (2). The most interesting feature of ionic
liquids is the extensive flexibility they offer in terms of alter-
ation of properties such as density, viscosity, Lewis acidity,
hydrophobicity, hydrophilicity, etc. (3). This feature of ionic
liquids has enabled chemists to design and engineer them so
that a proper equilibrium of properties is attained, making
them the most suitable and compatible solvents for several
chemical processes (4–8).
The significance of thioamides and their polyfunctional
Received 25 May 2003. Published on the NRC Research Press Web site at http://canjchem.nrc.ca on 22 September 2003.
P.U. Naik, S.J. Nara, J.R. Harjani, and M.M. Salunkhe.1 Department of Chemistry, The Institute of Science, 15 Madam Cama
Road, Mumbai 400 032, India.
1Corresponding author (e-mail: mmsalunkhe@hotmail.com).
Can. J. Chem. 81: 1057–1060 (2003)
doi: 10.1139/V03-152
© 2003 NRC Canada

1058
Can. J. Chem. Vol. 81, 2003
Scheme 1. The [bmim]Cl·AlCl3 (0.67 = N > 0.50) catalyzed ad-
dition of arenes to isothiocyanates.
form a charged complex containing electrophilic carbon
(16), which is believed to be involved as an intermediate in
its reaction with arenes.
Results and discussion
Over the last two years, our group has developed consid-
erable interest in investigating the Friedel–Crafts (17–19)
and condensation (20, 21) reactions in the Lewis acidic
chloroaluminate ionic liquids. As a part of our ongoing
venture to exploit chloroaluminate ionic liquids for newer
reactions, we present herein an account of the execution of
1-butyl-3-methylimidazolium chloroaluminate, [bmim]Cl·AlCl3
(0.67 ≥ N > 0.50; N is the apparent mole fraction of AlCl3 in
the ionic liquid) mediated addition of activated arenes to
isothiocyanates (Scheme 1).
We anticipated an exhortive result in the case of activated
arenes such as phenols, and they were therefore an obvious
choice for the preliminary investigations. A reaction per-
formed in [bmim]Cl did not fetch any product. The encour-
aging results obtained in the subsequent investigations
carried out in [bmim]Cl·AlCl3, N = 0.67, prompted us to
plan a systematic study aimed at the optimization of Lewis
acidity and stoichiometry of the ionic liquid and time of re-
action, to develop an ambient protocol for thioamidation.
2,5-Xylenol, being sufficiently reactive, was preferred as a
model substrate for these optimizations.
To study the effect of the Lewis acidity of
[bmim]Cl·AlCl3 (0.67 ≥ N ≥ 0.50) on the extent of product
formation, a series of ionic liquids with varying Lewis acidi-
ties were prepared. The molar proportion of 2,5-xylenol,
phenyl isothiocyanate, and ionic liquid was maintained at
1:1:1 at room temperature for 24 h, and the extent of conver-
sion in terms of the percentage yield of the product obtained
in each case was compared. The results reflected that an in-
crease in the Lewis acidity resulted in an increase in the per-
centage yield of product formed, but in all the cases the
yields were too low to be quantitative. The yield increased
from 0% to 30% as N increased from 0.50 to 0.63, progres-
sively, and only 64% yield was realized for [bmim]Cl·AlCl3,
N = 0.67.
The [bmim]Cl·AlCl3, N = 0.67, was an obvious choice for
all further investigations. With a view to obtain an optimal
yield of the product, we further planned to study the effect
of stoichiometry of [bmim]Cl·AlCl3, N = 0.67, on the extent
of product formation. A series of experiments were planned
in which the molar proportion of 2,5-xylenol and phenyl
isothiocyanate was fixed at 1:1 and varying amounts of
[bmim]Cl·AlCl3, N = 0.67, ranging from 1 to 2.5 mole
equivalents, was added. The reaction time was 24 h at room
temperature. The results indicated that the optimal product
formation calls for the use of at least 2 mole equivalents of
[bmim]Cl·AlCl3, N = 0.67. No significant increase in yields
was observed with a further increase in stoichiometry of the
ionic liquid.
tervals were compared. The results indicated that the optimal
time for the reaction is 8 h, beyond which no substantial in-
crease in yield was observed. No improvement in yield was
realized, even after a prolonged reaction time of 30 h.
To generalize the procedure and to study the effect of sub-
stituents on product formation, a variety of arenes were
screened under optimized conditions. The results obtained
are indicative of successful thioamidation of activated arenes
(Table 1). The reaction of phenyl isothiocyanate did not oc-
cur with benzene, but with m-xylene 83% yield of the prod-
uct was obtained. In terms of yields and selectivity, the
method is comparable to a nitromethane–AlCl3 system (13).
In general, aryl isothiocyanates fetched better yields than
alkyl isothiocyanates. In contrast to a number of classical
carbonylation procedures, an exquisite para-selectivity was
observed in reaction even with the arene that has both ortho
positions unblocked (entry 5). In the case of substrates with
the para position blocked, such as p-xylene and p-cresol, no
reaction was observed.
The present methodology can be easily extended to ortho
carbonylation of benzoic acids, i.e., conversion of benzoic
acids to phthalic acids and also for conversion of phthalic
acids to homophthalic acids, which are synthetically versa-
tile intermediates (22, 23). In addition, the method can serve
as an advantageous alternative to the synthesis of certain
benzoic acids and benzyl amines, which cannot be synthe-
sized by other methods.
Conclusion
In effect, we found 1-butyl-3-methylimidazolium chloro-
aluminate, [bmim]Cl·AlCl3 (N = 0.67), to be a homogenous
Lewis acidic medium for Friedel–Crafts type addition of ac-
tivated arenes to isothiocyanates, thus eliminating the use of
conventional obnoxious or volatile solvents such as halo-
genated hydrocarbons, nitromethane, and carbon disulphide.
Homogenous catalysis, reduced reaction times, ambient con-
ditions, and exquisite para-selectivity are some of distinc-
tively notable advantages offered by the novel procedure.
Experimental
The ionic liquids used in the present study were prepared
as per the procedures reported earlier (24, 25). In a typical
experimental procedure for thioamidation of arene, to the
weighed quantity of the arene (5 mmol) and isothiocyanate
(5 mmol), the ionic liquid [bmim]Cl·AlCl3 (N = 0.50–0.67,
5–15 mmol (as specified in the text)) was added, and the re-
action mixture was stirred for a specified time at room tem-
perature. All additions were carried out under a nitrogen
atmosphere glove box. The reactions were quenched with
6 mol L–1 HCl under cold conditions. The resultant solution
To optimize the time for the thioamidation procedure, a
series of experiments were planned in which the molar pro-
portion of 2,5-xylenol, phenyl isothiocyanate, and
[bmim]Cl·AlCl3 (N = 0.67) was maintained at 1:1:2 at room
temperature for different time periods (ranging from 2–
12 h). The yields of the product formed at different time in-
© 2003 NRC Canada

Naik et al.
1059
Table 1. The [bmim]Cl·AlCl3 (N = 0.67) mediated addition of arenes to isothiocyanates.
Note: Reactions carried out at room temperature for 8 h.
aIndicates isolated yields.
was extracted using ethyl acetate (3 × 10 mL). The com-
bined organic extracts were dried using anhydrous Na2SO4
and evaporated under reduced pressure to obtain the crude
product. The crude products were chromatographed using
silica gel column chromatography to yield pure thioamides,
which were characterized by physical constants, IR, and
© 2003 NRC Canada

1060
Can. J. Chem. Vol. 81, 2003
11. G. Balduzzi, F. Bigi, G. Casiraghi, G. Casnati, and G. Sartori.
Synthesis, 879 (1982).
12. O. Piccolo, L. Filippini, L. Tinucci, E. Valoti, and A. Citterio.
Tetrahedron, 42, 885 (1986).
NMR. The analytical and spectral data was consistent with
that reported in the literature (13).
13. T. Jagodzi½ski. Synthesis, 717 (1988) and references therein.
14. E.P. Papadopoulos. J. Org. Chem. 41, 962 (1976).
15. ². Drobnica, P. Kristián, and J. Augustín. In The chemistry of
cyanates and their thio derivatives. Part 2. Edited by S. Patai.
Wiley, New York. 1977. pp. 1003–1221.
References
1. See special issue on “ionic liquids”. Green Chem. 4, 73
(2002).
2. J. Dupont, R.F. de Souza, and P.A.Z. Suarez. Chem. Rev. 102,
3667 (2002).
16. T. Jagodzi½ski, E. Jagodzi½ska, and Z. Jab»o½ski. Tetrahedron,
42, 3683 (1986).
3. P. Wasserscheid and W. Keim. Angew. Chem., Int. Ed. Engl.
39, 3772 (2000).
17. J.R. Harjani, S.J. Nara, and M.M. Salunkhe. Tetrahedron Lett.
42, 1979 (2001).
4. A.C. Cole, J.L. Jensen, I. Ntai, K.L.T. Tran, K.J. Weaver, D.C.
Forbes, and J.H. Davis Jr. J. Am. Chem. Soc. 124, 5962
(2002).
5. C. Wheeler, K.N. West, C.L. Liotta, and C.A. Eckert. Chem.
Commun. 887 (2001).
6. Y. Ishida, H. Miyauchi, and K. Saigo. Chem. Commun. 2240
(2002).
7. P. Wasserscheid, A. Bösmann, and C. Bolm. Chem. Commun.
200 (2002).
8. J. van den Broeke, F. Winter, B.-J. Deelan, and G. van Koten.
Org. Lett. 4, 3851 (2002).
9. T. Jagodzi½ski. Chem. Rev. 103, 197 (2003) and references
therein.
18. S.J. Nara, J.R. Harjani, and M.M. Salunkhe. J. Org. Chem. 66,
8616 (2001).
19. S.S. Mohile, M.K. Potdar, and M.M. Salunkhe. Tetrahedron
Lett. 44, 1255 (2003).
20. M.K. Potdar, S.S. Mohile, and M.M. Salunkhe. Tetrahedron
Lett. 42, 9285 (2001).
21. J.R. Harjani, S.J. Nara, and M.M. Salunkhe. Tetrahedron Lett.
43, 1127 (2002).
22. P.A.S. Smith and R.O. Kan. J. Am. Chem. Soc. 82, 4753
(1960).
23. P.A.S. Smith and R.O. Kan. J. Org. Chem. 29, 2261 (1964).
24. J.S. Wilkes, J.A. Levisky, R.A. Wilson, and C.L. Hussey.
Inorg. Chem. 21, 1263 (1982).
10. J. Zabicky. In The chemistry of amides. Edited by S. Patai.
Wiley, New York. 1970. pp. 461–463.
25. A.K. Abdul-Sada, A.M. Greenway, K.R. Seddon, and T.
Welton. Org. Mass Spectrom. 28, 759 (1993).
© 2003 NRC Canada