Palladium-catalyzed synthesis of arylamines from aryl halides and lithium bis(trimethylsilyl)amide as an ammonia equivalent

Article abstract of DOI:10.1021/ol016333y

(Equation presented) A simple, palladium-catalyzed method to convert aryl halides to the parent anilines using lithium bis(trimethylsilyl)amide (LiN(SiMe₃)₂) is reported. The reaction is catalyzed by Pd(dba)₂ and P(t-Bu)₃ and can be run with as little as 0.2 mol % of catalyst. The reaction is faster than competing generation of benzyne intermediates and, therefore, provides the aniline products regiospecifically.

Full text of DOI:10.1021/ol016333y

ORGANIC
LETTERS
2001
Vol. 3, No. 17
2729-2732
Palladium-Catalyzed Synthesis of
Arylamines from Aryl Halides and
Lithium Bis(trimethylsilyl)amide as an
Ammonia Equivalent
Sunwoo Lee, Morten Jørgensen, and John F. Hartwig*
Department of Chemistry, Yale UniVersity, P.O. Box 208107,
New HaVen, Connecticut 06520-8107
john.hartwig@yale.edu
Received June 22, 2001
ABSTRACT
A simple, palladium-catalyzed method to convert aryl halides to the parent anilines using lithium bis(trimethylsilyl)amide (LiN(SiMe3)2) is
reported. The reaction is catalyzed by Pd(dba)2 and P(t-Bu)3 and can be run with as little as 0.2 mol % of catalyst. The reaction is faster than
competing generation of benzyne intermediates and, therefore, provides the aniline products regiospecifically.
Palladium-catalyzed aromatic C-N bond formation has
become a convenient and general method to form arylamines
from aryl halides and sulfonates.1-5 This reaction occurs with
a variety of primary amines, secondary amines, and related
nitrogen substrates such as hydrazones,6,7 carbamates,8
amides,9-11 and sulfoximines.12 However, this reaction does
not occur with ammonia and therefore does not form the
parent aniline. Instead, the formation of aniline has been
accomplished in two steps using ammonia surrogates, such
as allyl and diallylamine,13 benzyl and diphenylmethylamine,
and benzophenone imine.14,15 Some of these substrates
require metal-catalyzed cleavage of the protective group, and
others are relatively expensive. In contrast, bis(trimethyl-
silyl)amine or its deprotonated amide would be a less
expensive, but easily deprotected substrate to use as a
surrogate. Bis(trimethylsilyl)amides are common bases and
are available as solutions in hydrocarbon or ether solvents
or as solids.
Previous attempts to use these materials as a nitrogen
source were unsuccessful. In our experience, we had
observed little or no product from palladium-catalyzed
chemistry using arylphosphine ligands such as P(o-tolyl)3
or DPPF. When we did observe consumption of the aryl
halide, the process required elevated temperatures, low yields
were observed, and the silylamide product was formed as
two regioisomers. We reasoned that redox reactions and the
generation of benzyne intermediates occurred under these
conditions.16 Thus, simple, regiospecific conversion of an
aryl halide to an aniline would require milder temperatures
when using this reagent. While investigating the R-arylation
of esters to form products with quaternary carbons, we
observed competing formation of bis(trimethylsilyl)aryl-
amines from coupling of the bis(trimethylsilyl)amide base
with the aryl halide.17 Thus, we initiated a study to observe
the coupling of bis(trimethylsilyl)amide with aryl halides
exclusively. We report the results of this study, which
(1) Hartwig, J. F. In Modern Amination Methods; Ricci, A., Ed.; Wiley-
VCH: Weinheim, 2000.
(2) Hartwig, J. F. Angew. Chem., Int. Ed. 1998, 37, 2046.
(3) Hartwig, J. F. Synlett 1997, 329.
(4) Yang, B. H.; Buchwald, S. L. J. Organomet. Chem. 1999, 576, 125.
(5) Wolfe, J. P.; Wagaw, S.; Marcoux, J.-F.; Buchwald, S. L. Acc. Chem.
Res. 1998, 31, 805.
(6) Hartwig, J. F. Angew. Chem., Int. Ed. 1998, 37, 2090.
(7) Wagaw, S.; Yang, B.; Buchwald, S. J. Am. Chem. Soc. 1999, 121,
10251.
(8) Hartwig, J. F.; Kawatsura, M.; Hauck, S. I.; Shaughnessy, K. H.;
Alcazar-Roman, L. M. J. Org. Chem. 1999, 64, 5575.
(9) Shakespeare, W. Tetrahedron Lett. 1999, 40, 2035.
(10) Yang, B. H.; Buchwald, S. L. Org. Lett. 1999, 1, 35.
(11) Yin, J.; Buchwald, S. L. Org. Lett. 2000, 2, 1101.
(12) Bolm, C.; Hildebrand, J. P. J. Org. Chem. 2000, 65, 169.
(13) Jaime-Figueroa, S.; Liu, Y.; Muchowski, J. M.; Putman, D. G.
Tetrahedron Lett. 1998, 39, 1313.
(14) Mann, G.; Driver, M. S.; Hartwig, J. F. J. Am. Chem. Soc. 1998,
120, 827.
(15) Wolfe, J. P.; A° hman, J.; Sadighi, J. P.; Singer, R. A.; Buchwald, S.
L. Tetrahedron Lett. 1997, 38, 6367.
(16) Beller, M.; Breindl, C.; Riermeier, T. H.; Tillack, A. J. Org. Chem.
2001, 66, 1403.
10.1021/ol016333y CCC: $20.00 © 2001 American Chemical Society
Published on Web 07/19/2001

provides a simple method (eq 1) for the conversion of m-
and p-substituted aryl halides to anilines.
chemistry of aryl chlorides20 was not useful for this reaction.
Some of the ligands developed by Wolfe and Buchwald21
were suitable at high temperatures, but even the best ligand
for this substrate combination at room temperature was
inferior to P(t-Bu)3.
We evaluated the relative importance of countercation,
ligand:metal ratio, solvent, and equivalents of silylamide on
the reaction yields using 4-tert-butylbromobenzene as a
model substrate. Reactions with any of the alkali metal bis-
(trimethylsilyl)amides occurred in yields exceeding 95% by
GC. For consistency, we focused our studies on a single
alkali metal derivative, the least expensive lithium salt.
Unlike the reaction of amines with aryl halides,8 reactions
of the silylamide occurred with similar rates using 0.5:1, 1:1,
or 2:1 ratios of ligand to metal. Reactions occurred most
readily in alkane, arene, and dialkyl ether solvents. The
reactions were less facile in cyclic ether solvents such as
dioxane and THF, and they occurred in less than 20% yield
in DMF, mono- and diglyme, and weakly acidic solvents
such as acetonitrile. No excess silylamide was necessary to
observe high yields, although a slight excess of reagent was
not detrimental.
Table 1 summarizes reactions of lithium bis(trimethyl-
silyl)amide with 4-tert-butylbromobenzene catalyzed by
Table 1. Evaluation of Ligands for Aromatic C-N Coupling
of Lithium Bis(trimethylsilyl)amidea
In addition, we attempted to conduct reactions with the
silylamine in the presence of base instead of using the alkali
metal salts of the silylamine. Reactions in the presence of
sodium tert-butoxide base occurred, although in lower yield
than those conducted in the presence of the silylamide
directly. Reactions conducted with weaker bases, such as
Na3PO4 or Cs2CO3, which have been effective for reactions
of amines,8,22 gave no coupled product. Most likely, these
bases operate in the amination of aryl halides by deproto-
nating an arylpalladium complex with coordinated amine,
and the silylamide is too sterically hindered to effectively
bind palladium.
The scope of the reaction of lithium bis(trimethylsilyl)-
amide with aryl halides is presented in Table 2. The aryl
bis-silylamine product underwent hydrolysis during chro-
matography. Thus, the corresponding anilines, instead of the
silylamines, were isolated after addition of aqueous or
ethereal HCl and neutralization. The product from coupling
with 4-tert-butyl bromobenzene was, however, isolated in
its protected form by distillation.
With few exceptions, the reaction of m- and p-substituted
aryl bromides and chlorides gave high yields of the coupled
product. Electron-donating groups were tolerated. Electron-
withdrawing groups, such as a trifluoromethyl or an ester
group, would favor generation of benzyne intermediates.
However, substrates with electron-withdrawing groups re-
acted at low temperatures and generated the coupled product
regiospecifically in high yield. Aryl halides with esters in
conjugation with the aryl halide reacted cleanly at the halide
and not the ester.
palladium complexes of several ligands. These results show
that the first- and second-generation catalysts based on
arylphosphines gave little or no coupled product at low
temperatures. The catalyst system in entry 7 that is composed
of Pd(dba)2 and P(t-Bu)3, however, led to efficient formation
of the aryl silylamine product. It is the same system we have
recently used for room-temperature amination8 and carbonyl
R-arylation18 and is based on high-temperature work by
Nishiyama, Yamamoto, and Koie.19 The saturated carbene
ligand we recently used for room-temperature amination
(18) Kawatsura, M.; Hartwig, J. F. J. Am. Chem. Soc. 1999, 121, 1473.
(19) Nishiyama, M.; Yamamoto, T.; Koie, Y. Tetrahedron Lett. 1998,
39, 617.
(20) Stauffer, S. R.; Lee, S.; Stambuli, J. P.; Hauck, S. I.; Hartwig, J. F.
Org. Lett. 2000, 2, 1423.
(21) Wolfe, J. P.; Tomori, H.; Sadighi, J. P.; Yin, J. J.; Buchwald, S. L.
J. Org. Chem. 2000, 65, 1158.
(17) Lee, S.; Hartwig, J. F. Unpublished results.
(22) Wolfe, J. P.; Buchwald, S. L. Tetrahedron Lett. 1997, 38, 6359.
2730
Org. Lett., Vol. 3, No. 17, 2001

benzyne and possibly radical intermediates would be gener-
ated. However, the high activity of the catalyst derived from
Pd(dba)2 and P(t-Bu)3 allowed for reaction of the aryl
chlorides under relatively mild conditions. The results in
Table 2 show that many aryl chlorides underwent regiospe-
cific reaction with bis(trimethylsilyl)amide to form the parent
aniline in high yield. In general, the substrate scope for
reactions of aryl chlorides was similar to that for reactions
of aryl bromides, but reactions required heating to occur at
reasonable rates.
Table 2. Scope of the Aromatic C-N Coupling of Lithium
Bis(trimethylsilyl)amide Using P(t-Bu)3 and Pd(dba)2 (1:1)a
Aryl bromides or chlorides possessing enolizable hydro-
gens did not couple with the bis(trimethylsilyl)amide reagent.
These substrates react by ketone R-arylation,18,23 and presum-
ably the haloacetophenones generate polymeric or oligomeric
products during reaction with the silylamide reagent. In
addition, this catalyst system did not allow for reactions of
aryl halides with nitro groups, and reactions of those with
p- or m-cyano groups were sluggish. Perhaps direct reaction
of the strong base with these substrates interferes with the
desired palladium-catalyzed coupling.
Although the process occurred in a fairly general fashion
for substrates substituted with meta and para substituents,
the reaction did not occur with substrates bearing ortho
substituents. These substrates are some of the most effective
for reactions with simple amine reagents. However, the
silylamide reagent is apparently too bulky to react with the
sterically hindered arylpalladium(II) intermediate. For con-
version of these substrates to the parent amine, reaction with
a different ammonia equivalent13-15 is necessary at this time.
In addition to evaluating reaction scope, we assessed
reactions conducted with low catalyst loadings. Table 3
summarizes these results. Reactions with lower loadings did
require higher temperatures, but evidently these temperatures
were still low enough to prevent generation of benzyne
intermediates.
In some cases high turnover numbers were obtained. For
example, 4-tert-butylbromobenzene and 3-bromoanisole
formed the coupled product in 89% and 91% yields with
only 0.2 mol % of catalyst at 70 °C, and 2-bromo-6-
methoxynaphthalene reacted in 92% yield with only 0.1 mol
% of catalyst. Reactions of aryl chlorides also occurred with
lower loadings than the 5% used in the reactions of Table 2,
but generally 0.5-1 mol % of catalyst was still necessary
for full conversion at temperatures low enough to generate
single regioisomeric products.
We also evaluated each reaction in the absence of catalyst
at temperatures up to 120 °C. In only a few cases did we
see any aniline product at all. 3-Bromoanisole and the
dioxolane in entry 14 gave 10% and 6% of the aniline after
12 h at 70 °C, and 4-butylbromobenzene and 4-bromoben-
zophenone gave roughly 40% and 30% yields after 12 h at
120 °C. Although the protected bromocatechol in entry 18
gave a reasonable 53% yield under these conditions, this
yield for the high-temperature, uncatalyzed reaction was
much lower than the 99% yield observed at 70 °C using 1%
palladium catalyst.
Aryl chlorides are generally less reactive than bromides
and often require higher temperatures for reaction. If this
were the case for reactions of the silylamide reagent, then
(23) Fox, J. M.; Huang, X. H.; Chieffi, A.; Buchwald, S. L. J. Am. Chem.
Soc. 2000, 122, 1360.
Org. Lett., Vol. 3, No. 17, 2001
2731

are commercially available as a solution in hydrocarbon
solvents and can, therefore, be delivered to the reaction
solution by syringe.
Table 3. Aromatic C-N Coupling of Lithium
Bis(trimethylsilyl)amide at Low Loadings of P(t-Bu)3 and
Pd(dba)2 (1:1)a
Alternatively, the preformed Pd(0) catalyst Pd[P(t-Bu)3]2
is commercially available and is air stable. Combining this
air-stable species with the air-stable and commercially
available Pd(dba)2 or Pd2(dba)3 in a 1:1 molar ratio to metal,
as done previously by Fu,24 generates a catalyst that is more
active than Pd[P(t-Bu)3]2, albeit less active than the catalyst
generated in situ from Pd(dba)2 and P(t-Bu)3. Use of 2.5 mol
% of these two catalyst precursors gave 92% yield of the
aryl silylamine after 24 h at room temperature for reaction
of 4-tert-butylbromobenzene with lithium bis(trimethylsilyl)-
amide.
The mechanistic data we have obtained for the reactions
of aryl bromides are not straightforward, but the data for
reactions of aryl chlorides are simpler to interpret. 31P NMR
spectra obtained for reactions of aryl chlorides using a 1:1
ratio of Pd(dba)2 and P(t-Bu)3 show that the Pd(0) complex
Pd[P(t-Bu)3]2 is the major palladium-phosphine complex
in solution. Roughly 20 h after consumption of the aryl
chloride, 40% cyclometalated complex25,26 is formed. In
contrast, little Pd[P(t-Bu)3]2 is observed during the reaction
of aryl bromides. Two identified complexes with chemical
shifts 10-20 ppm upfield of those of the free ligand were
observed by 31P NMR spectrometry. These are not formed
by reaction of aryl halide or by reaction of the silylamide
with Pd[P(t-Bu)3]2. Further studies will be needed to
determine the structures of these species.
In conclusion, we have shown that the recently developed
catalysts for aryl halide amination now allow for the reaction
of lithium bis(trimethylsilyl)amide with m- and p-substituted
aryl bromides at temperatures low enough to form products
exclusively from palladium-catalyzed coupling without for-
mation of benzyne intermediates. This catalytic chemistry,
therefore, forms products from regiospecific replacement of
the halogen by silylamide. After aqueous workup, this
reaction generates the parent aniline.
Acknowledgment. We thank the NIH (R29-6M-55382)
for support of this work and Neil A. Beare for helpful
discussions.
Supporting Information Available: Reaction procedures
and characterization of new reaction products. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL016333Y
(24) Littke, A.; Dai, C.; Fu, G. J. Am. Chem. Soc. 2000, 122, 4020-
4028.
(25) Clark, H. C.; Goel, A. B.; Goel, R. G.; Goel, S.; Ogini, W. O. Inorg.
Chim. Acta 1978, L441.
Although the ligand and silylamide reagent used in the
catalytic reaction are air sensitive, convenient procedures can
be followed without a drybox. Both the silylamide and ligand
(26) Geissler, H.; Gross, P.; Guckles, B. Ger. Patent, DE 19647584, 1998.
2732
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