Facile N-Arylation of Amines and Sulfonamides

Article abstract of DOI:10.1021/ol0358612

(Matrix presented) A facile, transition-metal-free N-arylation procedure for amines and sulfonamides has been developed, which affords good to excellent yields of arylated products under very mild reaction conditions. A methoxy-substituted aryl triflate affords N-arylated products in high yields with excellent regioselectivity. This chemistry tolerates a variety of functional groups.

Full text of DOI:10.1021/ol0358612

ORGANIC
LETTERS
2003
Vol. 5, No. 24
4673-4675
Facile N-Arylation of Amines and
Sulfonamides
Zhijian Liu and Richard C. Larock*
Department of Chemistry, Iowa State UniVersity, Ames, Iowa 50011
larock@iastate.edu
Received September 24, 2003
ABSTRACT
A facile, transition-metal-free N-arylation procedure for amines and sulfonamides has been developed, which affords good to excellent yields
of arylated products under very mild reaction conditions. A methoxy-substituted aryl triflate affords N-arylated products in high yields with
excellent regioselectivity. This chemistry tolerates a variety of functional groups.
Establishing an efficient, reliable methodology for the
N-arylation of amines and sulfonamides is currently an active
area in organic synthesis. Such subunits are commonly
encountered in biologically active compounds,1 agrochemi-
cals,2 and compounds of interest in material science.3
Traditionally, the preparation of arylamines has been carried
out under Ullmann-type conditions involving the coupling
of amines with aryl halides.4 Although these copper-promoted
reactions are useful, they are usually performed at high
temperatures and the yields are not very reproducible.5
Recently, Buchwald has reported significant improvements
in this chemistry.6 Buchwald7 and Hartwig8 have also
demonstrated that the palladium-catalyzed N-arylation of a
variety of amines by aryl halides is a powerful method for
the synthesis of arylamines. Despite these significant recent
improvements, there still are limitations in present N-ary-
lation methodology. For example, it is still difficult to prepare
N-arylated sulfonamides9 and present N-arylation methodol-
ogy may not accommodate certain organic functionality. Of
the functional groups that are incompatible with the Cu- or
Pd-catalyzed N-arylation methodology, the most important
are probably halides and sulfonates,10 epoxides,11 and prob-
ably carbon-carbon triple bonds. Thus, a simple and general
procedure to generate N-arylated products from a variety of
(1) (a) Negwer, M. In Organic-Chemical Drugs and their Synonyms:
(An International SurVey), 7th ed., Akademie Verlag GmbH: Berlin, 1994.
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10.1021/ol0358612 CCC: $25.00 © 2003 American Chemical Society
Published on Web 10/24/2003

Table 1. Facile N-Arylation of Amines and Sulfonamidesa
a Reaction conditions: 0.25 mmol of amine or sulfonamide is allowed to react with the number of equivalents of aryl triflate and CsF shown in the Table
and 4.0 mL of MeCN as solvent at room temperature.
amines and sulfonamides, which can tolerate a wide variety
of functional groups, remains elusive.
Recently, aryl triflate 1a12 has been employed to generate
benzyne, which can easily undergo a variety of electro-
philic,13 nucleophilic,13 and cycloaddition reactions.14 Nitrogen-
containing compounds, such as azirines,15 oxazoles,16 pyr-
roles,17 and imidazoles,18 are known to react with arynes to
afford N-arylation products. However, the N-arylation of
amines19 and sulfonamides by arynes has not been widely
(13) (a) Yoshida, H.; Honda, Y.; Shirakawa, E.; Hiyama, T. Chem.
Commun. 2001, 1880-1881. (b) Yoshida, H.; Shirakawa, E.; Honda, Y.;
Hiyama, T. Angew. Chem., Int. Ed. 2002, 41, 3247-3249.
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1214.
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Org. Lett., Vol. 5, No. 24, 2003

studied due to the difficulty in generating arynes under
convenient reaction conditions.
Diarylation products are also readily obtained in excellent
yields when an excess of the silylaryl triflate is employed
with primary amines (entries 3, 4, and 7-10). A wide variety
of alkyl- and arylamines undergo efficient coupling. It should
be pointed out that a variety of functional groups, including
halides, hydroxyl groups, and carbon-carbon double and
triple bonds, survive under our reaction conditions (entries
5-9). A hydroxyl-substituted amine (entry 9) has been
observed to react selectively with the NH2 group, instead of
the OH group, to afford the corresponding diarylation product
in a good yield, although an 8% yield of the O-arylation
product was isolated as a side product. Furthermore, we can
selectively prepare secondary or tertiary arylamines by simply
changing the ratio of the reactants (compare entries 1 and 3,
and 2 and 4). As expected, a secondary amine can also be
arylated in an excellent yield (entry 11).
Herein we report the facile, transition-metal-free N-ary-
lation of amines and sulfonamides by the reaction of silylaryl
triflates with a variety of amines and sulfonamides. The new
procedure is characterized by the following features: (1) The
mild base CsF is employed. (2) The reaction is run at room
temperature. (3) The procedure works well with a variety of
amines and sulfonamides, affording good to excellent yields.
We first allowed 2-(trimethylsilyl)phenyl triflate (1a) to
react with CsF and 1.2 equiv of aniline in acetonitrile at room
temperature for 20 h. Diphenylamine was obtained in an 81%
yield (Scheme 1), and only a trace of triphenylamine was
isolated (Table 1, entry 1).
Although some effort has been devoted recently to the
N-arylation of sulfonamides, the scope of this chemistry with
respect to either the sulfonamide or the aryl halide is still
very limited.9,21 As shown in Table 1, entries 12-15, alkane-
and arenesulfonamides both efficiently undergo N-arylation
under our reaction conditions. Using primary sulfonamides
and an excess of triflate, one obtains the corresponding
diarylation products in high yield. Unfortunately, we have
been unable to effect simple monoarylation of sulfonamides
such as RSO2NH2. The methoxy-substituted silylaryl triflate
1b also reacts cleanly with p-toluenesulfonamides to afford
a high yield and excellent regioselectivity (entry 14). One
can also start with secondary sulfonamides and produce the
corresponding tertiary sulfonamides in excellent yield (entry
15).
We have also investigated the use of carboxamides to
generate N-arylamides, employing the silylaryl triflate 1a and
CsF at room temperature. Unfortunately, only low yields of
the corresponding N-arylamides could be obtained.
In summary, we have developed an efficient, mild, tran-
sition-metal-free method for the N-arylation of amines and
sulfonamides. A variety of functional groups are compatible
with the reaction conditions. The regioselectivity of the
methoxy-substituted aryl triflate 1b is excellent. Further
studies into the scope of different heteroatom-containing
substrates and silylaryl triflates are currently underway in
our laboratories.
Scheme 1
This methodology can be applied to the N-arylation of a
variety of primary amines (Table 1, entries 1-10). Excess
aniline reacts smoothly with aryl triflate 1a and CsF to give
the corresponding secondary amine in an 81% yield (entry
1). It is noteworthy that o-iodoaniline also reacts with aryl
triflate 1a to generate the desired iodo-substituted product
in an 83% isolated yield (entry 5). Thus, halides are readily
accommodated by our reaction conditions. The methoxy-
substituted silylaryl triflate 1b also reacts cleanly with aniline
to generate a single isomer in good yield with excellent
regioselectivity (entry 2). This regioselectivity can be readily
explained by steric and electronic effects, both of which favor
nucleophilic attack at the position meta to the methoxy group
of the aryne.18,20 Silylaryl triflate 1a also reacts with an excess
of propargylamine to afford a 62% yield of the secondary
N-arylated amine and 15% of the diarylated amine was also
isolated (entry 6).
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Acknowledgment. We are grateful to the Petroleum
Research Fund, administered by the American Chemical
Society, for their generous financial support.
Supporting Information Available: Detailed experi-
mental procedures and characterization data for all previously
unknown products. This material is available free of charge
via the Internet at http://pubs.acs.org.
(20) Kessar, S. V. In ComprehensiVe Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon Press: Oxford, England, 1991; Vol. 4, pp 483-
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Yin, J.; Buchwald, S. L. Org. Lett. 2000, 2, 1101-1104.
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