Pd-catalyzed O-arylation of ethyl acetohydroximate: Synthesis of O-arylhydroxylamines and substituted benzofurans

Article abstract of DOI:10.1021/ja1044874

An efficient Pd catalyst for the O-arylation of ethyl acetohydroximate with aryl chlorides, bromides, and iodides has been developed. Ethyl acetohydroximate serves as an efficient hydroxylamine equivalent for C-O cross-coupling, thereby allowing for the p

Full text of DOI:10.1021/ja1044874

Published on Web 07/06/2010
Pd-Catalyzed O-Arylation of Ethyl Acetohydroximate: Synthesis of
O-Arylhydroxylamines and Substituted Benzofurans
Thomas J. Maimone and Stephen L. Buchwald*
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139
Received May 24, 2010; E-mail: sbuchwal@mit.edu
Table 1. Ligand Evaluationa
Abstract: An efficient Pd catalyst for the O-arylation of ethyl
acetohydroximate with aryl chlorides, bromides, and iodides has
been developed. Ethyl acetohydroximate serves as an efficient
hydroxylamine equivalent for C-O cross-coupling, thereby allowing
for the preparation of O-arylhydroxylamines from simple aryl halides.
Short reaction times and broad substrate scope, including heteroaryl
coupling partners, allow access to O-arylhydroxylamines that would
be difficult to prepare in a single step by traditional methods.
Moreover, the O-arylated products so formed can be directly
transformed into substituted benzofurans in a single operation.
Entry
Ligand
Conversionb
Entry
Ligand
Conversionb
1
2
3
1
3
4
100%
70%
51%
4
5
6
2
5
6
0%
0%
0%
a PhBr (1.5 mmol), ethyl acetohydroximate (1.9 mmol), Cs2CO3 (2.3
mmol), (allylPdCl)2 (0.5 mol %), Ligand (2 mol %), toluene (3 mL), 65
°C, 1 h. b Determined by GC.
Owing to their facile incorporation into a variety of bioactive oxime
linkages,1 use as tagging elements for library synthesis,2 and function
as key starting materials for the synthesis of benzofurans,3 O-
arylhydroxylamines (aryloxyamines) represent valuable synthetic
building blocks. Historically, this motif has been constructed via SNAr-
type processes of various hydroxylamine equivalents (e.g., N-hydroxy-
phthalimide, ethyl acetohydroximate) with highly electron-deficient
aromatic systems, including arene-metal complexes.4 In addition,
N-transfer reagents have also been employed to form the N-O linkage
from the corresponding phenol.5 Given the limited generality in these
processes, recent emphasis has been placed on the copper-mediated
construction of Ar-ON(R) bonds. Maitra and Wailes have reported
the coupling of oximes with aryl iodides catalyzed by a CuI/1,10-
Phenanthroline system.6 In addition, both Huang and Meyer have
reported the coupling of oximes with arylboronic acids utilizing Cu(II)
salts.7 To date, however, it is perhaps the copper-mediated coupling
of aryl boronic acids with N-hydroxyphthalimide, reported by Sharpless
and Kelly, that represents the most general route to O-arylhydroxy-
lamines.8 We envisioned that a Pd-catalyzed coupling of simple aryl
halides with a suitable hydroxylamine equivalent (Figure 1) could
potentially address many of the shortcomings of the aforementioned
Cu-based methodologiessnamely low to moderate yields, long reaction
times, difficulty with substrates containing ortho-substituents, lack of
heterocyclic substrates, and the necessity to employ aryl iodides or
arylboronic acids as coupling partners. Herein, we report a Pd-catalyzed
method that utilizes commercially available ethyl acetohydroximate
as the hydroxylamine equivalent. The O-arylated products so formed
can easily be cleaved with aqueous acid to produce O-arylhydroxy-
lamines or directly processed to substituted benzofurans.
PhBr with ethyl acetohydroximate (Table 1). Ligands 3 and 4 which
have previously been employed in Pd-catalyzed C-O coupling
processes between aryl halides and alcohols or phenols could be
employed for this transformation, albeit with diminished ef-
ficiency.10 Ligand 6, which lacks the tri-isopropyl groups, as well
as ligands 2 and 5 which do not contain the di-tert-butyl phosphine
moiety, were all ineffective under these conditions. The high activity
displayed with 1 was crucial due to both the thermal sensitivity of
the product N-O linkage,11 and the ability of Pd(0) to oxidatively
add into this bond at elevated temperatures.12
The generality of the coupling process is shown by the examples
in Table 2. Aryl chlorides, bromides, and iodides could all be
employed, with aryl bromides being optimal and electron-rich aryl
chlorides being most problematic.13 Using 1% Pd,14 2% 1, and Cs2CO3
as base, many electron-neutral or -deficient aryl bromides were found
to undergo complete conversion within 1 h at 65 °C in toluene. The
couplings of 1,4-bromochlorobenzene and 1,2-bromofluorobenzene
were performed on scales of 5 and 10 mmol, respectively. In addition,
a variety of heteroaryl halides including pyridinyl, quinolinyl, pyrim-
idinyl, and benzothiazolyl were found to readily undergo coupling.
Heterocycles containing acidic N-H groups, such as indoles and
imidazoles, have proven problematic to date. We have found that for
aryl bromides containing ortho-alkyl substituents, the use of ligand 4
gives superior results to that with 1, presumably due to its smaller
size. Using this system even hindered substrates with an isopropyl or
phenyl group in the ortho position undergo efficient coupling (Table
2). The O-arylated products can be easily hydrolyzed to the free
oxyamines by exposure to aqueous HCl (Table 3).
A survey of biarylphosphine ligands revealed that a catalyst based
on t-BuBrettPhos9 (1) was highly active in the cross-coupling of
O-Arylketoximes bearing acidic R-hydrogens are known to rear-
range to benzofurans via a [3,3] sigmatropic process, closely paralleling
the venerable Fischer indole synthesis.3 Of interest to us was the
Figure 1. Desired transformation.
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9990 J. AM. CHEM. SOC. 2010, 132, 9990–9991
10.1021/ja1044874  2010 American Chemical Society

C O M M U N I C A T I O N S
Table 4. One-Pot Synthesis of Benzofuransa
Table 2. Palladium-Catalzyed O-Arylation of Ethyl Acetohydroximatea
a Oxime (1 equiv), ketone (2 equiv), H2O (5 equiv), HCl (4 M in
dioxane, 5 equiv), 1,4-dioxane (0.2 M), 70 °C, 1-2 h; isolated yield,
average of two runs on a 0.5-1.0 mmol scale.
postdoctoral fellowship to T.J.M. (1F32GM088931). We thank
Chemetall for a generous gift of Cs2CO3.
Supporting Information Available: Procedural and spectral data. This
material is available free of charge via the Internet at http://pubs.acs.org.
a ArX (1 mmol), Ethyl Acetohydroximate (1.25 mmol), Cs2CO3 (1.5
mmol), (allylPdCl)2 (0.5-2.5 mol %), 1 or 4 (2-10 mol %), PhMe (2
mL), 65 °C, 1-12 h; isolated yields, average of two or more runs.
b Yield on a 10 mmol scale ) 87%. c Yield on a 5 mmol scale ) 88%.
References
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a Oxime (1 equiv), HCl (6 M in H2O, 2 equiv), 1,4-dioxane (0.5 M), 0 °C
f rt, 1 h; isolated yields, average of two runs on a 0.5-1.0 mmol scale.
prospect of directly converting the products of the Pd-coupling into
benzofurans in a process reminiscent of our prior work in the Fischer
indolization.15 After significant experimentation, we found that expo-
sure of the O-arylated ethyl acetohydroximate product to an exogenous
ketone and H2O in HCl/dioxane at 70 °C produces the corresponding
benzofuran in synthetically useful yields (Table 4).
In summary, a hydroxylamine equivalent has been developed
for Pd-catalyzed C-O cross-coupling. Key to the success of this
reaction was the use of bulky biarylphosphine ligands 1 and 4,
which promote C-O reductive elimination under relatively mild
conditions. Broad substrate scope and short reaction times make
this an attractive method to prepare highly substituted O-arylhy-
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(13) We have observed the following trend in rate of C-O coupling: PhBr >
PhI > PhCl.
(14) The use of Pd2(dba)3 gives similar results to (allylPdCl)2.
(15) (a) Wagaw, S.; Yang, B. H.; Buchwald, S. L. J. Am. Chem. Soc. 1998,
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Acknowledgment. We thank the National Institutes of Health
(NIH) for financial support of this project (GM-58160) and a
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