ORGANIC
LETTERS
2001
Vol. 3, No. 21
3417-3419
New Ammonia Equivalents for the
Pd-Catalyzed Amination of Aryl Halides
Xiaohua Huang and Stephen L. Buchwald*
Department of Chemistry, Massachusetts Institute of Technology,
Cambridge, Massachusetts 02139
Received August 31, 2001
ABSTRACT
LiN(SiMe3)2, Ph3SiNH , and LiNH can be be used as ammonia equivalents for the Pd-catalyzed coupling of aryl halides. Using these amine
2
2
derivatives, simple anilines, including ortho-substituted ones, as well as di- and triarylamines can be readily prepared.
During the past few years, great progress has been made in
the development of the Pd-catalyzed amination of aryl
halides.1 As a result, a wide variety of arylamines can now
be efficiently prepared using this methodology. The use of
ammonia, the simplest amine, has not yet been reported,
however, presumably for reasons of safety and convenience.2
We previously reported that benzophenone imine can func-
tion as an effective ammonia equivalent.3-5 Coupling reac-
tions with this imine are high yielding and can be performed
under extremely mild reaction conditions. Moreover, the
resulting N-aryl imines can be cleaved using several or-
thogonal methods that are compatible with a variety of
protecting groups. Recently, Hartwig described the use of
LiN(SiMe3)2 (LiHMDS) as an ammonia equivalent.6 He
showed that this nucleophile could be used with an impres-
sive range of aryl halide substrates. Moreover, many of these
transformations could be carried out at room temperature
and/or with low catalyst loadings. This report has prompted
us to disclose our own work in this area, the majority of
which was carried out prior to this recent disclosure.
While investigating the coupling of hindered amines with
aryl halides, we queried whether LiHMDS might be useful
as an ammonia surrogate. We were pleased to find that, in
many instances, it functions well in this role. Shown in Table
1 are a few examples of the Pd-catalyzed preparation of
primary anilines. These reactions were typically performed
using 0.5 mol % Pd2(dba)3 (1% Pd) and 1.2 mol % of the
air-stable, commercially available ligand 1.7 Although solid
LiHMDS could be employed for this chemistry, it requires
the use of a glovebox. We found that comparable results
(1) (a) Hartwig, J. F. Angew. Chem., Int. Ed. Engl. 1998, 37, 2046-
2067. (b) Hartwig, J. F.; Kawatsura, M.; Hauck, S. I.; Shaughnessy, K. H.;
Alcazar-Roman, L. M. J. Org. Chem. 1999, 64, 5575-5580. (c) Yang, B.
H.; Buchwald, S. L. J. Organomet. Chem. 1999, 576, 125-146. (d) Wolfe,
J. P.; Buchwald, S. L. J. Org. Chem. 2000, 65, 1144-1157. (e) Wolfe, J.
P.; Tomori, H.; Sadighi, J. P.; Yin, J.; Buchwald, S. L. J. Org. Chem. 2000,
65, 1158-1174 and references therein.
(2) Ammonia has been used in the Cu-catalyzed amination of 2-bro-
mopyridines: Lang, F.; Zewge, D.; Houpis, I. N.; Volante, R. P. Tetrahedron
Lett. 2001, 42, 3251-3254.
(3) (a) Wolfe, J. P.; Åhman, J.; Sadighi, J. P.; Singer, R. A.; Buchwald,
S. L. Tetrahedron Lett. 1997, 38, 6367-6370. See also: (b) Mann, G.;
Hartwig, J. F.; Driver, M. S.; Fernandez-Rivas, C. J. Am. Chem. Soc. 1998,
120, 827-828.
(6) Lee, S.; Jørgensen, M.; Hartwig, J. F. Org. Lett. 2001, 3, 2729-
2732.
(4) For other ammonia equivalents in Pd-catalyzed aminations, see: (a)
Hori, K.; Mori, M. J. Am. Chem. Soc. 1998, 120, 7651-7652. (b) Jaime-
Figueroa, S.; Liu, Y.; Muchowski, J. M.; Putman, D. G. Tetrahedron Lett.
1998, 39, 1313-1316. (c) Lim, C. W.; Lee, S. Tetrahedron 2000, 56, 5131-
5136. (d) Bolm, C.; Hildebrand, J. P. Tetrahedron Lett. 1998, 39, 5731-
5734
(5) In situ generated CuHMDS has been used in the stoichiometric
amination of aryl iodides: King, F. D.; Walton, R. M. J. Chem. Soc., Chem.
Commun. 1974, 256-257.
(7) General Procedure A. An oven-dried resealable Schlenk tube was
charged with Pd2(dba)3 (4.6 mg, 5.0 µmol, 0.50 mol %) and 2-dicyclo-
hexylphosphinobiphenyl (1) (4.2 mg, 12 µmol, 1.2 mol %). The Schlenk
tube was evacuated and back-filled with argon. Aryl halide (1.0 mmol)
and LiHMDS (1.2 mL, 1 M solution in THF, 1.2 mmol) were added via
syringe. The Schlenk tube was then sealed with a Teflon screw cap and
placed in a preheated oil bath at 65 °C for 15 h. After cooling of the reaction
mixture to room temperature, aqueous HCl (5 mL, 1 M) was added, and
the mixture was stirred at room temperature for 5 min. The solution was
10.1021/ol0166808 CCC: $20.00 © 2001 American Chemical Society
Published on Web 09/26/2001