Copper-catalyzed N-arylation of sulfonamides with aryl bromides and iodides using microwave heating

Article abstract of DOI:10.1016/S0040-4039(03)00569-0

The copper-catalyzed N-arylation of sulfonamides with a variety of aryl bromides and iodides using microwave heating is described.

Full text of DOI:10.1016/S0040-4039(03)00569-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 3385–3386
Copper-catalyzed N-arylation of sulfonamides with aryl bromides
and iodides using microwave heating
Huan He and Yong-Jin Wu*
Bristol-Myers Squibb Pharmaceutical Research Institute, 5 Research Parkway, Wallingford, CT 06492, USA
Received 3 February 2003; revised 25 February 2003; accepted 27 February 2003
Abstract—The copper-catalyzed N-arylation of sulfonamides with a variety of aryl bromides and iodides using microwave heating
is described. © 2003 Elsevier Science Ltd. All rights reserved.
N-Arylsulfonamides are important compounds, partic-
ularly in pharmaceutical research. A number of them
have been reported to have significant biological activ-
ity, e.g. class III antiarrhythmic agents,1 non-nucleotide
reverse transcriptase inhibitors,2 nonpeptidic vaso-
pressin V1a receptor antagonists,3 and HIV-1 protease
inhibitors.4 As such, significant efforts have gone into
the development of efficient methods for their
preparation.
aryl halides has not yet been reported. This report
describes our preliminary studies on the copper-cata-
lyzed N-arylation of sulfonamides using microwave
heating.
Treatment of iodobenzene with 2 equiv. benzenesulfon-
amide in the presence of copper(I) iodide (10 mol%)
and potassium carbonate (2 equiv.) in N-methylpyrro-
lidinone at 195°C for 3 h under microwave irradiation
provided N-phenylbenzenesulfonamide in 90% yield,
after purification of the crude product using silica gel
flash chromatography (Table 1, entry 1). As a control
experiment, the same reaction mixture was heated at
195°C for 3 h in a sealed tube using an oil bath, and the
product was obtained in 50% yield. This observation
demonstrates the advantage of microwave radiation
over conventional heating techniques. As shown in
Table 1, these conditions worked well for a variety of
aryl iodides (entries 2–4) and bromides (entries 5–9). It
should be pointed out that the coupling reactions with
aryl iodides (entries 1–4) generally provide better yields
than those with the corresponding bromides (entries
5–8). To test the scope of this reaction, bromobenzene
was treated with methanesulfonamide (entry 10), p-
toluenesulfonamide (entry 11) and the secondary sul-
fonamide N-methylbenzenesulfonamide (entry 12)
under the above conditions, and the yields were com-
parable to that obtained with benzenesulfonamide. Of
special note is that the yield of the reaction was not
greatly influenced by the presence of electron-donating
or electron-withdrawing groups on the aryl halides.
However, this type of N-arylation does not seem to
work on aryl chlorides. For example, treatment of
benzenesulfonamide with chlorobenzene in the presence
of copper(I) iodide (10 mol%) and potassium carbonate
(2 equiv.) provided very little product even after 20 h
microwave heating.
The most straightforward routes to N-arylsulfonamides
involve the direct formation of the arylꢀnitrogen bond.
The traditional protocols for N-arylation of sulfon-
amides prescribe simple copper salts or often copper
metal as the catalyst and usually require drastic reac-
tion conditions.5 Due to this drawback which limits its
scope, the copper-catalyzed N-arylation of sulfon-
amides with aryl halides has not been recognized as a
powerful synthetic methodology in organic synthesis.
Recently, Buchwald and co-workers5,6 reported the pal-
ladium-catalyzed coupling of aryl halides with several
sulfonamides. Lam and co-workers7 also described the
synthesis of N-arylsulfonamides through the copper-
catalyzed N-arylation of sulfonamides with arylboronic
acids. In a recent medicinal chemistry program, we
found that microwave heating can be used to facilitate
the N-arylation of sulfonamides.8 Microwave irradia-
tion has become increasingly popular in recent years to
improve the yield and shorten reaction times in a
variety of reactions9 including the Goldberg reaction,10
the copper-catalyzed amidation of aryl halides. How-
ever, to our knowledge, the microwave-mediated
methodology on the N-arylation of sulfonamides with
* Corresponding author. Tel.: +1-203-677-7485; fax: +1-203-677-7702;
e-mail: yong-jin.wu@bms.com
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00569-0

3386
H. He, Y.-J. Wu / Tetrahedron Letters 44 (2003) 3385–3386
Table 1. N-Arylation of sulfonamides with aryl halides
References
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8. The microwave unit used in our experiments is the Smith
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11. Representative procedure: To a solution of iodobenzene
(102 mg, 0.5 mmol) and benzenesulfonamide (157 mg, 1
mmol) in N-methylpyrrolidinone (0.67 mL) in a vial were
added potassium carbonate (138 mg, 1 mmol), and cop-
per(I) iodide (9.5 mg, 0.05 mmol). The vial was sealed
and heated by microwave at 195°C for 3 h. The reaction
mixture was cooled to room temperature and filtered
through a pad of Celite. The filtrate was evaporated in
vacuo, and the residue was purified by silica gel flash
chromatography (20% acetone/80% hexanes) to give N-
phenylbenzenesulfonamide (105 mg, 90%) as an oil. 1H
NMR (CDCl3, 400 MHz) l 6.88 (1H, br. s), 7.07 (2H, d,
J=8.0 Hz), 7.10 (1H, t, J=8.0 Hz), 7.23 (1H, t, J=8.0
Hz), 7.24 (1H, d, J=8.0 Hz), 7.42 (2H, t J=8.0 Hz), 7.52
(1H, t, J=8.0 Hz), 7.78 (2H, d, J=8.0 Hz); 13C NMR
(CDCl3, 100 MHz) l 121.8, 125.5, 127.2, 129.0, 129.4,
133.0, 136.4, and 139.0. The spectroscopic data is in full
agreement with that obtained from an authentic sample
purchased from Aldrich.
In summary, we have developed an operationally sim-
ple and efficient method for the N-arylation of sulfon-
amides with a variety of aryl bromides and iodides.11