C O M M U N I C A T I O N S
Table 6. Pd-Catalyzed Amination in Water
significantly expanded the substrate scope of Pd-catalyzed aromatic
amination, and reported the first examples of the Pd-catalyzed
amidation of arenesulfonates and the first aqueous amination
protocols that do not necessitate the use of cosolvents. Further uses
of 1 will be reported in due course.
Acknowledgment. We thank the National Institutes of Health
(GM 45906) for supporting this work. We are grateful to Pfizer,
Merck, Lundbeck, and Rhodia Pharmaceutical Solutions for ad-
ditional unrestricted support. D.Z. thanks CNPq for a postdoctoral
fellowship. L.J. was supported as a postdoctoral trainee of the
National Cancer Institute (NCI Training Grant CI T32CA09112).
We are also grateful to Mr. Joseph R. Martinelli for developing a
procedure for the preparation of ligand 1.
Supporting Information Available: Experimental procedures and
characterization data for all unknown compounds (PDF). This material
References
(1) Reviews: (a) Muci, A. R.; Buchwald, S. L. Top. Curr. Chem. 2002, 219,
131. (b) Hartwig, J. F. In Handbook of Organopalladium Chemistry for
Organic Synthesis; Negishi, E., Ed.; Wiley-Interscience: New York, 2002;
p 1051.
(2) Wolfe, J. P.; Tomori, H.; Sadighi, J. P.; Yin, J.; Buchwald, S. L. J. Org.
Chem. 2000, 65, 1158.
(3) While we previously reported that the use of the strong base LiN(TMS)2
could offer a partial solution to this problem, this was both experimentally
complicated and still had a fairly narrow substrate scope (e.g., no primary
aliphatic amines, no acyclic secondary amines): Harris, M. C.; Huang,
X.; Buchwald, S. L. Org. Lett. 2002, 4, 2885.
(4) Old, D. W.; Wolfe, J. P.; Buchwald, S. L. J. Am. Chem. Soc. 1998, 120,
9722.
(5) (a) Hamann, B. C.; Hartwig, J. F. J. Am. Chem. Soc. 1998, 120, 7369. (b)
Hartwig, J. F.; Hamann, B. C. U.S. Patent 6,235,938, 2001. Ni-catalyzed
coupling of sulfoximines with aryl tosylates: (c) Bolm, C.; Hildebrand,
J. P.; Rudolph, J. Synthesis 2000, 911.
(6) Ligand 1 is commercially available from Strem Chemical. (a) Kaye, S.;
Fox, J. M.; Hicks, F. A.; Buchwald, S. L. AdV. Synth. Catal. 2001, 343,
789. (b) Tomori, H.; Fox, J. M.; Buchwald, S. L. J. Org. Chem. 2000,
65, 5334.
(7) Wagaw, S.; Yang, B. H.; Buchwald, S. L. J. Am. Chem. Soc. 1999, 121,
10251.
(8) Only a few examples of the coupling of amides with aryl triflates have
been disclosed, cf.: Yin, J.; Buchwald, S. L. J. Am. Chem. Soc. 2002,
124, 6043.
a For 8 h at 100 °C. b With 2.5 mol % of ligand 1. c With 2.5 mol % of
t-Bu3PH+BF4- as ligand. d From aryl nonaflate; for 16 h at 80 °C. e From
aryl tosylate; with 1 mol % of 10 as catalyst.
A consistently problematic class of substrates has been secondary
amides derived from haloanilines. We have now found that the use
of ligand 1 allows the Pd-catalyzed coupling of a wide range of
amines with meta and para amidohalobenzenes in good-to-excellent
yield (Table 5). K2CO3 in t-BuOH is optimal for the arylation of
anilines; however, many alkylamines require a stronger base, NaOt-
Bu, in either t-BuOH or toluene. Another troublesome class of aryl
halide substrates are those bearing a primary amide. We find that
the addition of p-anisidine to 3-chlorobenzamide proceeds in good
yield indicating, for the first time, that the chemistry is compatible
with a halide substrate containing a primary amide. Substrates
containing free carboxylic acid groups have, to date, failed to be
transformed to coupling products by Pd-catalyzed amination. As
can be seen, this now can be accomplished for aromatic carboxylic
acids with the carboxylic acid group being either on the aryl halide,
the aniline, or both. We believe, in this case, that the key is to
have sufficient solubility of the carboxylic acid-containing substrates
under the basic reaction conditions that are employed.
(9) For a Pd-catalyzed oxidation reaction accelerated by t-BuOH as a
cosolvent, see: Bagdanoff, J. T.; Ferreira, E. M.; Stolz, B. M. Org. Lett.
2003, 5, 835.
(10) In preliminary experiments, primary and secondary alcohols provided poor
results while tert-amyl alcohol was a suitable solvent.
(11) Klapars, A.; Huang, X.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124,
7421.
(12) Klapars, A.; Antilla, J. C.; Huang, X.; Buchwald, S. L. J. Am. Chem.
Soc. 2001, 123, 7727.
(13) (a) Kwong, F. Y.; Buchwald, S. L. Org. Lett. 2003, 5, 793. (b) Kwong,
F. Y.; Klapars, A.; Buchwald, S. L. Org. Lett. 2002, 4, 581.
(14) Aqueous hydroxide as a base for palladium-catalyzed amination has been
reported; however, a phase transfer catalyst and toluene cosolvent were
required: (a) Kuwano, R.; Utsunomiya, M.; Hartwig, J. F. J. Org. Chem.
2002, 67, 6479. For the use of solid NaOH in dioxane, see: (b) Grasa, G.
A.; Viciu, M. S.; Huang, J.; Nolan, S. P. J. Org. Chem. 2001, 66, 7729.
(15) Although not investigated in detail, we found in one case that t-Bu3PH+-
BF4- could be used instead of 1 with comparable results. (a) Nishiyama,
M.; Yamamoto, T.; Koie, Y. Tetrahedron Lett. 1998, 39, 617. (b)
Netherton, M. R.; Fu, G. C. Org. Lett. 2001, 3, 4295.
(16) The palladacycle 10 could be successfully used in other amination reactions
as well. Nevertheless, Pd2dba3/1 is more convenient and therefore
recommended in the majority of cases. For studies on palladacycles of
this type, see: Bedford, R. B.; Cazin, C. S. J.; Coles, S. J.; Gelbrich, T.;
Horton, P. N.; Hursthouse, M. B.; Light, M. E. Organometallics 2003,
22, 987.
As the use of KOH in t-BuOH oftentimes gave superior results,
we decided to examine the use of water as a “solvent” for amina-
tions using no cosolvent.14 The use of 1/Pd2dba3 and KOH in water
in many cases gives excellent results.15 Table 6 demonstrates the
amination of aryl chlorides containing nitro, trifluoromethyl, and
pyridyl groups. Additionally, we have shown that indole can be
arylated in high yield. Interestingly, we have also been able to
aminate a hindered aryl nonaflate in good yield. Even an aryl
tosylate could be arylated employing the aqueous conditions
although in this case the palladacycle 10, incorporating ligand 1,
had to be used instead of the combination of Pd2dba3 and 1.16
In summary, we have developed the first general catalytic system
for the amination of aryl sulfonates other than triflates or nonaflates,
JA035483W
9
J. AM. CHEM. SOC. VOL. 125, NO. 22, 2003 6655