SCHEME 1. Microwave-Enhanced Nucleophilic
Substitution Reactions
Revisiting Nucleophilic Substitution Reactions:
Microwave-Assisted Synthesis of Azides,
Thiocyanates, and Sulfones in an Aqueous
Medium
Yuhong Ju,† Dalip Kumar,‡ and Rajender S. Varma*,†
one of the emerging nonconventional methods being recognized
as viable environmentally benign alternatives.5
Clean Processes Branch, Sustainable Technology DiVision,
National Risk Management Research Laboratory,
U.S. EnVironmental Protection Agency, 26 West Martin Luther
King DriVe, MS 443, Cincinnati, Ohio 45268, and
Chemistry Group, Birla Institute of Technology and Science,
Pilani 333031, Rajasthan, India
In the continuation of our studies on microwave-assisted
organic synthesis in an aqueous medium,4 we have broadened
our interest to nucleophilic substitution reactions which could
possibly be accelerated under this alternative mode of activation.
Herein, we wish to report the nucleophilic substitution reaction
of alkyl halides or tosylates using readily available alkali azides,
thiocyanates, and sulfinates under microwave irradiation that
proceed safely and efficiently in aqueous media for the
preparation of various azides, thiocyanates, and sulfones
(Scheme 1).
ReceiVed May 31, 2006
Organic azides, an important class of energy-rich and flexible
intermediate compounds,6 have drawn considerable interest since
the late 19th century.7 Industrial interest in organic azides began
with the use of azides as a precursor for the synthesis of amines8
and heterocycles such as triazoles and tetrazoles9 as well as their
application as blowing agents and functional groups in phar-
maceuticals as exemplified by azidonucleosides in the treatment
of AIDS10 and their bioconjugation via Staudinger ligation.11
The most common route to alkyl azides involves the classic
nucleophilic substitution reaction of alkyl halides with inorganic
azides6c but suffers from complex procedures,12 long reaction
A practical, rapid, and efficient microwave (MW) promoted
synthesis of various azides, thiocyanates, and sulfones is
described in an aqueous medium. This general and expedi-
tious MW-enhanced nucleophilic substitution approach uses
easily accessible starting materials such as halides or tosylates
in reaction with alkali azides, thiocyanates, or sulfinates in
the absence of any phase-transfer catalyst, and a variety of
reactive functional groups are tolerated.
(2) (a) Varma, R. S. AdVances in Green Chemistry: Chemical Syntheses
Using MicrowaVe Irradiation; AstraZeneca Research Foundation India:
Bangalore, India, 2002. (b) Gabriel, S. C.; Gabriel, S.; Grant, E. H.; Halstead,
B. S. J.; Mingos, D. M. P. Chem. Soc. ReV. 1998, 27, 213. (c) Loupy, A.,
Ed. MicrowaVes in Organic Synthesis; Wiley-VCH: Weinheim, 2002. (d)
Varma, R. S. Green Chem. 1999, 1, 43. (e) de la Hoz, A.; D´ıaz-Ortiz, A’.;
Moreno, A. Chem. Soc. ReV. 2005, 34, 164. (f) Varma, R. S. MicrowaVe
Technology - Chemical Applications: Kirk-Othmer Encyclopedia of
Chemical Technology, 5th ed.; John Wiley & Sons: New York, 2004.
(3) (a) Kappe, C. O. Angew. Chem., Int. Ed. 2004, 43, 6250. (b) Jachuck,
R. J. J.; Selvaraj, D. K.; Varma, R. S. Green Chem. 2006, 8, 29. (c) Bose,
A. K.; Manhas, M. S.; Ganguly, S. N.; Sharma, A. H.; Banik, B. K. Synthesis
2002, 1578. (d) Baghurst, D. R.; Mingos, D. M. P. Chem. Soc. ReV. 1991,
20, 1. (e) Leadbeater, N. E. Chem. Commun. 2005, 2881. (f) An, J.; Bagnell,
L.; Cablewski, T.; Strauss, C. R.; Trainor, R. W. J. Org. Chem. 1997, 62,
2505.
(4) (a) Ju, Y.; Varma, R. S. Org. Lett. 2005, 7, 2409. (b) Ju, Y.; Varma,
R. S. J. Org. Chem. 2006, 71, 135. (c) Ju, Y.; Varma, R. S. Green Chem.
2004, 6, 219.
(5) (a) Varma, R. S.; Naicker, K. P. Tetrahedron Lett. 1998, 39, 2915.
(b) Varma, R. S.; Naicker, K. P.; Kannan, P.; Aschberger, J. Synth. Commun.
1999, 29, 2823. (c) Varma, R. S.; Naicker, K. P.; Kumar, D. J. Mol. Catal.
A: Chem. 1999, 149, 153.
(6) (a) Smith, P. A. S. Org. React. 1946, 3, 337. (b) Boyer, J. H.; Canter,
F. C. Chem. ReV. 1954, 54, 1. (c) Scriven, E. F. V.; Tumbull, K. Chem.
ReV. 1988, 88, 297.
(7) (a) Grieâ, P. Philos. Trans. R. Soc. London 1864, 13, 377. (b) Curtius,
T. Ber. Dtsch. Chem. Ges. 1890, 23, 3023.
(8) Rao, H. S. P.; Siva, P. Synth. Commun. 1994, 24, 549.
(9) (a) Bra¨se, S.; Gil, C.; Knepper, K.; Zimmermann, V. Angew. Chem.,
Int. Ed. 2005, 44, 5188. (b) Kolb, H. C.; Sharpless, K. B. Drug DiscoVery
Today 2003, 8, 1128.
(10) Lin, T. S.; Prusoff, W. H. J. Med. Chem. 1978, 21, 109.
(11) Kohn, M.; Breinbauer, R. Angew. Chem., Int. Ed. 2004, 43, 3106.
(12) (a) Lieber, E.; Chao, T. S.; Rao, C. N. R. J. Org. Chem. 1957, 22,
238. (b) Ito, M.; Koyakumaru, K.; Ohta, T.; Takaya, H. Synthesis 1995,
376.
Reactions in aqueous media are of paramount importance in
organic syntheses.1 The use of many toxic and volatile organic
solvents, particularly chlorinated hydrocarbons, as reaction
media contributes pollution to the environment, and it is highly
desirable to develop environmentally benign processes that can
be conducted in aqueous media. Furthermore, using water as a
solvent offers many advantages such as simple operation and
high efficiency in many organic reactions that involve water-
soluble substrates and reagents. Organic reactions assisted by
microwave (MW) irradiation have attracted considerable atten-
tion in the past two decades for the efficient and relatively
friendlier synthesis of a variety of organic compounds.2
Developing efficient, selective, and eco-friendly synthetic
methods for applications in organic synthesis is an ongoing
program in our research group.1c,e,2a,d Utilization of water as
reaction media3 in conjunction with microwave irradiation4 is
* To whom correspondence should be addressed. Tel: (+1-513) 487-2701.
Fax: (+1-513) 569-7677.
† U.S. Environmental Protection Agency.
‡ Birla Institute of Technology and Science.
(1) (a) Li, C. J. Chem. ReV. 2005, 105, 3095. (b) Organic Synthesis in
water; Grieco, P. A., Ed.; Blackie: London, 1998. (c) Wei, W.; Keh, C. C.
K.; Li, C. J.; Varma, R. S. Clean Technol. EnViron. Policy 2005, 7, 62. (d)
Narayan, S.; Muldoon, J.; Finn, M. G.; Fokin, V. V.; Kolb, H. C.; Sharpless,
K. B. Angew. Chem., Int. Ed. 2005, 44, 3275. (e) Skouta, R.; Varma, R. S.;
Li, C. J. Green Chem. 2005, 7, 571.
10.1021/jo061114h CCC: $33.50 © 2006 American Chemical Society
Published on Web 07/28/2006
J. Org. Chem. 2006, 71, 6697-6700
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