J. S. Yada6 et al. / Tetrahedron Letters 44 (2003) 2217–2220
2219
In this paper [bmim]PF6 ionic liquid is proved to be a
useful and novel reaction media for aromatic amina-
tion, avoiding the use of basic and highly polar organic
solvents such as DMF, DMI or DMSO and high
temperature reaction conditions by playing the dual
role of solvent and promoter. The substrates show
significant increase in reactivity thus improving the
yields substantially. The experimental procedure is
quite simple, convenient and avoids tedious aqueous
work-up procedures for the isolation of products. The
use of an easily accessible and recyclable ionic liquid
makes this procedure convenient, economic and user-
friendly.
In view of the emerging importance of imidazolium-
based ionic liquids as novel reaction media, we wish to
explore the use of ionic liquids as promoters and recy-
clable solvent systems for the synthesis of arylamines
under mild conditions (Scheme 1).
The treatment of p-nitrobromobenzene with morpho-
line in 1-butyl-3-methylimidazolium hexafluorophos-
phate ionic liquid resulted in the formation of
4-(4-nitrophenyl)morpholine in 87% yield. 1-Butyl-3-
methylimidazolium hexafluorophosphate ([bmim]PF6)
ionic liquid was prepared according to reported proce-
dures.11 In a similar fashion, a variety of aryl halides
reacted smoothly with a range of secondary amines
under these reaction conditions to give the correspond-
ing arylamines in excellent yields (Table 1). The reac-
tions proceeded efficiently at room temperature in ionic
liquids whereas conventional methods require high tem-
perature or microwave activation.12 The scope and
generality of this process is illustrated with respect to
various amines and aryl chlorides, bromides and
fluorides bearing ortho- or para-nitro or -cyano groups
and the results are presented in Table 1.13 This method
is even effective with sterically hindered and highly
functionalized aryl halides (entries a, b, c, g, i). Acid
sensitive functionalities such as carbamates, esters and
ethers survived under these conditions. Secondary alkyl
amines such as morpholine, piperidine, pyrrolidine and
piperazine showed higher reactivity than their acyclic
counterparts. Furthermore, the reactions proceeded
rapidly with o- and p-nitro substituted benzenes when
compared to cyano substituted aryl halides. The experi-
mental procedure is very simple and convenient and in
addition, this method did not require any aqueous
work-up thereby avoiding the generation of toxic waste.
Since the products were weakly soluble in the ionic
liquid, they were easily separated by simple extraction
with ether. The rest of the viscous ionic liquid was
thoroughly washed with ether and recycled in subse-
quent reactions. Second runs using recovered ionic
liquid afforded similar yields to those obtained in the
first runs. However, in the third and fourth runs, the
yields gradually decreased. For example, p-nitrobro-
mobenzene and piperidine in [bmim]PF6 afforded 90,
90, 81, and 78%, over four cycles. However, the activity
of the ionic liquid was consistent in runs and no
decrease in yield was obtained when amine was used in
slight excess (1.5 equiv.). The products obtained were of
the same purity as in the first run. [Bmim]BF4 ionic
liquid was also found to be equally effective for this
conversion. Finally, the efficiency of various quaternary
ammonium salts was studied. This nucleophilic substi-
tution reaction was not successful when n-tetra-
butylammonium chloride (n-Bu4NCl) or 1-n-butyl-3-
methylimidazolium chloride ([bmim]Cl) were used
as solvents. This indicated that both cation and anion
play an important role in this transformation.
The simple experimental and product isolation proce-
dures combined with ease of recovery and reuse of this
novel reaction media is expected to contribute to the
development of green strategies for the synthesis of
arylamines.
Acknowledgements
B.V.S. and A.K.B. thank CSIR, New Delhi for the
award of fellowships.
References
1. (a) Terrier, F. Nucleophilic Aromatic Displacements: The
Influence of the Nitro Group; VCH Publishers: New York,
1991; p. 376; (b) Belfield, A. J.; Brown, G. R. Tetrahedron
1999, 55, 13285–13300; (c) Frost, C. G.; Mendonca, P. J.
Chem. Soc., Perkin Trans. 1 1998, 2615–2623.
2. Belfield, A. J.; Brown, G. R.; Foubister, A. J. Tetra-
hedron 1999, 55, 11399–11428.
3. (a) Fuller, R. W.; Maso, N. R.; Melloy, B. B. Biochem.
Pharm. 1980, 29, 833; (b) Broekkamp, C. L. E.; Leysen,
D. B.; Peeters, W. M. M.; Pinder, R. M. J. Med. Chem.
1995, 38, 4615–4633.
4. (a) Cho, Y. H.; Park, J. C. Tetrahedron Lett. 1997, 38,
8331–8334; (b) Brown, G. R.; Foubister, A. J.; Ratcliffe,
P. D. Tetrahedron Lett. 1999, 40, 1219–1222.
5. (a) Ibata, T.; Isogami, Y.; Toyoda, J. Chem. Lett. 1987,
1187–1190; (b) Kotski, H.; Sakai, H.; Shinohara, T.
Synlett 2000, 116–118.
6. (a) Guram, A. S.; Rennels, R. A.; Buchwald, S. L.
Angew. Chem., Int. Ed. Engl. 1995, 34, 1348–1350; (b)
Wolfe, J. P.; Wagaw, S.; Buchwald, S. L. J. Am. Chem.
Soc. 1996, 118, 7215–7216.
7. (a) Hartwig, J. F. Synlett 1997, 329–340; (b) Hartwig, J.
F. Angew. Chem., Int. Ed. Engl. 1998, 37, 2046–2067.
8. Recent reviews on ionic liquids: (a) Welton, T. Chem.
Rev. 1999, 99, 2071–2083; (b) Wasserscheid, P.; Keim, W.
Angew. Chem., Int. Ed. 2000, 39, 3772–3789.
9. Catalytic reactions in ionic liquids: (a) Sheldon, R. Chem.
Commun. 2001, 2399–2407; b) Gordon, C. M. Appl.
Catal. A: Gen. 2001, 222, 101–117.
10. (a) Cole, A. C.; Jensen, J. L.; Ntai, I.; Tran, K. L. T.;
Weaver, K. J.; Forbes, D. C.; Davis, J. H., Jr. J. Am.
Chem. Soc. 2002, 124, 5962–5963; (b) Peng, J.; Deng, Y.
Tetrahedron Lett. 2001, 42, 5917–5919.
11. Preparation of ionic liquids: (a) Park, S.; Kazlauskas, R.
J. J. Org. Chem. 2001, 66, 8395–8401; (b) BonhOte, P.;
Dias, A. P.; Papageorgiou, N.; Kalyanasundaram, K.;
Gratzel, M. Inorg. Chem. 1996, 35, 1168–1178.
12. (a) Salmora, G. V.; Dall’Oglio, E.; Zucco, C. Tetrahedron
Lett. 1998, 39, 2471–2474; (b) Jaisinghani, H. G.;
Khadilkar, B. M. Tetrahedron Lett. 1997, 38, 6875–6876.
Yadav
