M. Anbazhagan et al. / Tetrahedron Letters 43 (2002) 4221–4224
4223
required for reaction with O-methylhydroxylamine.21
Consequently, it was necessary to prepare the O-
methylbenzamidoximes 3 by an indirect approach,
References
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which involved the O-methylation of
1
using
methylsulfate.22
Palladium-catalyzed coupling of the O-methylbenzami-
doximes proceeded smoothly using Pd2(dba)3, Xant-
phos and Cs2CO3 in dioxane to give the desired
N-aryl O-methylbenzamidoximes (Scheme 1). Prelimi-
nary studies of the effect of catalyst, ligand and base
on the course of the reaction were performed using
O-methyl-4-chlorobenzamidoxime
and
4-bromo-
toluene. The coupling reaction failed to proceed when
Pd2(dba)3/BINAP or Pd(OAc)2/Xantphos were used as
catalyst/ligand, and also when K2CO3 was used as
base in place of Cs2CO3. The scope and limitations of
the reaction was thus further explored using the initial
coupling conditions.
As shown in Table 1, the coupling with para- and
meta-substituted aryl halides containing various elec-
tron attracting groups or moderate electron donating
groups proceeded to give isolated yields ranging from
61 to 87%.23,24 Coupling with an ortho-substituted
halide gave a significantly lower isolated yield (26%,
entry 3), however, this was much improved with an
activated substrate (64%, entry 4). A catalyst/ligand
loading of 2–3 mol% was generally required for suffi-
cient reactivity with most examples, although in one
case, 1 mol% gave high yield with an activated halide
(entry 9). Coupling with 2-bromothiophene (entry 13)
and 2-bromopyridine (entry 14) failed under our stan-
dard conditions, with the latter also failing to couple
with a CuI catalyst system25 that has been used with
nitrogen heterocycles. In contrast, coupling with the
highly electron deficient 5-nitro-2-chloropyridine led to
diarylation of nitrogen in an 81% yield based on aryl
halide (entry 12). Finally, with 4-bromo- and 4-
iodoanisole (entries 15 and 16), no isolable amount of
coupling product was observed, which is consistent
with the diminished reactivity found with this catalyst
system in the N-arylation of amides14 and ureas16 with
electron rich halides.
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19. The thermal elimination of hydroxylamine from ami-
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In conclusion, we have described a straightforward
method for the synthesis of N-aryl O-methylbenzami-
doximes employing the Pd-catalyzed coupling of O-
methylbenzamidoximes and aryl halides. Under these
conditions, both benzamidoxime and O-acetyl benza-
midoxime failed to undergo N-arylation and formed
other products.
Acknowledgements
This work was supported by awards from NIH
(Grants NIAID RO1AI 46365, RO1GM61587, R44
AI40518-02), Immtech International, Inc. and the Bill
and Melinda Gates Foundation.
20. Ooi, N. S.; Wilson, D. A. J. Chem. Soc., Perkin Trans.
2 1980, 1792.