Palladium-catalyzed amination of aromatic C-H bonds with oxime esters

Article abstract of DOI:10.1021/ja100676r

"Chemical equation presented" We report a conceptually new approach to the direct amination of aromatic C-H bonds. In this process, an oxime ester function reacts with an aromatic C-H bond under redox-neutral conditions to form, in the case studied, an indole product. These reactions occur with relatively low catalyst loading (1 mol %) by a mechanism that appears to involve an unusual initial oxidative addition of an N-O bond to a Pd(0) species. The Pd(II) complex from oxidative addition of the N-X bond has been isolated for the first time, and evidence for the intermediacy of such oxidative addition products in the catalytic reaction has been gained.

Full text of DOI:10.1021/ja100676r

Published on Web 02/26/2010
Palladium-Catalyzed Amination of Aromatic C-H Bonds with Oxime Esters
Yichen Tan and John F. Hartwig*
Department of Chemistry, UniVersity of Illinois at Urbana-Champaign, 600 South Mathews AVenue,
Urbana, Illinois 61801
Received January 25, 2010; E-mail: jhartwig@illinois.edu
Table 1. Selected Conditions for C-H Bond Aminationa
Aromatic amines and their derivatives are common in pharmaceu-
ticals, agrochemicals, dyes, herbicides, and conducting polymers.1
Therefore, intense effort has been focused on the development of
methods for the synthesis of the C-N bonds in aromatic amines.
Traditional routes to aromatic amines by nitration, reduction, and
alkylation have been largely displaced by catalytic amination of aryl
halides and pseudohalides.2 However, the direct amination of C-H
bonds3 would provide a complementary approach to the synthesis of
arylamines by eliminating the need to prepare the aryl halides or
pseudohalides. Two general strategies for the direct amination of C-H
bonds have been followed: formal insertion of a nitrene into an
aromatic C-H bond (strategy A in Scheme 1)4 and oxidative amination
of arenes with amine derivatives (strategy B in Scheme 1).5 In the
former, a highly active nitrene intermediate is involved, and in the
latter, an external oxidant is required; both processes typically require
high catalyst loadings (5-20%).
We envisioned an alternative approach to the direct amination of
C-H bonds based on reactions of hydroxylamine derivatives6 as the
nitrogen source (strategy C in Scheme 1). Such reactions would be an
umpolung of the amination of aryl halides, operate under overall redox-
neutral conditions, and occur by a manifold outside of that with nitrene
intermediates. Thus, a range of complexes could catalyze this process,
and conditions with low catalyst loadings could ultimately be achieved.
Herein, we describe our initial results on a Pd-catalyzed amination of
aromatic C-H bonds with oxime esters, in this case to form indole
products. Our data support a mechanism operating by an unusual initial
oxidative addition of a N-O bond to Pd(0), the product of which has
been isolated for the first time.
entry
catalyst
base
time (h)
yield (%)c
1
2
3
4
Pd(dba)2 (100 mol %)
Pd(dba)2 (10 mol %)
Pd(dba)2 (1 mol %)
Pd(PCy3)2 (1 mol %)
-
K3PO4
Cs2CO3
Cs2CO3
4
24
24
24
70
74
72
56
a The reactions were conducted on 0.05 mmol scale in 1 mL of
toluene. b Dried in a furnace at 500 °C. c GC yields.
We hypothesized that stoichiometric amounts of palladium were
needed because the acetic acid side product was consuming the
potential catalyst. Thus, further reactions with catalytic amounts of
Pd(dba)2 were conducted in the presence of bases, and these experi-
ments (see the Supporting Information) showed that reactions con-
ducted with K3PO4 or Cs2CO3 as the base (Table 1, entries 2 and 3)
formed the cyclized product 2a in good yield. Moreover, reactions
with just 1 mol % Pd(dba)2 as the catalyst and Cs2CO3 as the base
occurred in the same yields as reactions with stoichiometric amounts
of Pd(dba)2. Reactions conducted with phosphine-ligated Pd(0) catalysts
resulted in lower yields of 2a than those catalyzed by Pd(dba)2.
Nevertheless, the reaction catalyzed by 1 mol % Pd(PCy3)2 formed
the indole product in 56% yield after 24 h.
Having developed conditions for the catalytic amination of aromatic
C-H bonds with oxime esters, we conducted reactions with substrates
that would test the effect of steric and electronic influences on the
functionalization process and the potential of this approach to provide
indoles with substitution patterns that are less accessible by traditional
routes (Table 2). Reactions of substrates containing meta substituents
(1d and 1e) to test the regioselectivity of this cyclization revealed a
strong dependence on the substituents. A 1:1.1 mixture of isomers (2d)
was isolated from the reaction of a substrate containing m-methyl
groups. However, a single isomer (2e) was isolated from the reaction
of a substrate containing m-methoxy groups, and for reasons we do
not fully understand, this isomer was formed by reaction at the more
sterically hindered position ortho to this group.
Scheme 1. General Strategies for Direct Amination
We began our study by investigating the cyclization of the oxime
acetate 1a derived from 1,1-diphenylacetone to form 2-methyl-3-
phenylindole (2a) from a combination of C-H amination and
tautomerization (Table 1, entry 1). The oxidative addition of the N-O
bond in an oxime ester to Pd(0) was proposed but not directly observed
in previous studies of amino-Heck reactions,7 and the resulting Pd(II)
species would be similar to the Pd(II) carboxylate intermediates
proposed to cleave aromatic C-H bonds during reactions catalyzed
by Pd(OAc)2.3c,5 After a survey of reaction variables, we found that
oxime acetate 1a formed indole 2a after 4 h in toluene at 150 °C in
good yield when a stoichiometric amount of Pd(dba)2 was used.
Reactions conducted with other Pd complexes formed 2a in lower
yields under the same conditions.8
To study the effects of the electronic properties of substituents on
the C-H amination process, cyclizations of a series of substrates
containing groups in the para position (1f-k) were studied. These
results showed that electron-withdrawing substituents had little effect
on the yield of the C-H amination. Greater than 60% yields of the
indole products 2g-j were obtained. However, reaction of substrate
1k containing electron-donating groups occurred in lower yield. Aryl
chlorides and bromides were inert under these reaction conditions,
implying that the Pd(0) catalyst preferentially reacts with the N-O
bond of the oxime acetate over the carbon-halogen bonds. Finally,
substrates 1l and 1m also underwent cyclization in moderate yields,
indicating that the gem-diaryl substructure was not required for the
C-H amination process to occur, although the monocyclic substrate
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3676 J. AM. CHEM. SOC. 2010, 132, 3676–3677
10.1021/ja100676r  2010 American Chemical Society

C O M M U N I C A T I O N S
1b containing an ethyl group as R2 reacted in lower yield than the
of complex 3 to form indole 2a suggests that an acetate analogue of
3 would form the indole product under the conditions of the catalytic
process. Thus, our data are consistent with the mechanism proposed
in Scheme 2.
substrates containing a methyl group as R2.9
Table 2. Pd-Catalyzed Cyclization of Oxime Acetatesa b
,
Scheme 3. Isolation and Reaction of the Product of Oxime Addition
In summary, we have demonstrated a novel approach to the direct
amination of aromatic C-H bonds using oxime esters under redox-
neutral conditions. These reactions occur with relatively low catalyst
loadings through a Pd(II) complex generated from N-O bond oxidative
addition. Such a complex has been isolated for the first time, and
evidence for its intermediacy in the catalytic reaction has been gained.
Further investigations of the mechanism and an expansion of this
methodology to intermolecular amination of aromatic C-H bonds are
ongoing in our laboratory.
a Reactions were conducted on 0.1 mmol scales in 10 mL of toluene.
b Isolated yields.
Acknowledgment. This work is dedicated to the memory of Keith
Fagnou. We thank the NSF for financial support through the Center
for Enabling New Technologies through Catalysis (CENTC), CHE-
0650456, and Profs. William D. Jones and Wes T. Borden for helpful
suggestions.
On the basis of previous studies of amino-Heck reactions7 and
C-H amination conducted with Pd(OAc)2,3c,5 we envisioned that
the cyclization of 1a could occur by oxidative addition of the N-O
bond to Pd(0) followed by tautomerization to generate complex II
(Scheme 2). Subsequent C-H bond cleavage would form palla-
dacyclic complex III. C-N bond-forming reductive elimination
from III would afford the indole product 2a and regenerate the
active Pd(0) catalyst. Alternatively, the C-H bond-cleavage step
could occur prior to the tautomerization.
Supporting Information Available: Experimental procedures, spectra
for all compounds, and crystallographic data for 3 (CIF). This material is
available free of charge via the Internet at http://pubs.acs.org.
References
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Scheme 2. Proposed Catalytic Cycle
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To assess whether N-O bond oxidative addition could be the first
step of the catalytic cycle, we sought to isolate a complex generated
from N-O bond oxidative addition. Because of the difficulty of
isolating Pd(II) products with dba as the sole ancillary ligand, we
conducted mechanistic studies with complexes ligated by PCy3, which
were shown to catalyze the cyclization process (see above). Indeed,
the reaction of an oxime ester containing a pentafluorobenzoyl group
(1n) with a stoichiometric amount of Pd(PCy3)2 provided Pd(II)
complex 3 in high yield (Scheme 3). The structure of 3 was determined
by X-ray diffraction.8 Complex 3 is the first isolated complex formed
by oxidative addition of an N-X bond (X ) N, O, halide) to Pd(0).10
The reaction of oxime ester 1a catalyzed by 1 mol % of isolated
complex 3 formed indole 2a in a yield (58%) similar to that for the
reaction of 1a catalyzed by 1 mol % Pd(PCy3)2 (56%, see above). In
addition, heating complex 3 at 150 °C in toluene with added Cs2CO3
provided 2a in 31% yield (Scheme 3). Although the yields do not
exactly match those for the reactions of oxime acetates because the
pentafluorobenzoate complex 3 is not the precise intermediate I in the
proposed catalytic cycle for reaction of these substrates, the reaction
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