NꢀX bonds and to achieve compatibility with different
functional groups. Therefore, our studies have focused
on the in situ formation of arynes via 1,2-elimination of
o-TMS-aryl triflates promoted by mildly basic fluoride
(Scheme 1).9 This paper describes our development of a
one-pot protocol that begins with simple amines to directly
prepare o-haloaminoarenes under transition-metal-free
conditions. This transformation exhibits a good compat-
ibility with functional groups and a broad substrate scope
of arynes, including substituted arynes and heteroarynes.
The observed regioselectivity for haloamination of arynes
suggests the insertion may occur through a polar pathway
directed by steric and electronic effects of both arynes and
NꢀX bonds.
Scheme 1. Synthetic Strategies to Access o-Haloaminoarenes
Our studies began with exploring the direct benzyne
insertion with N-chloramines, which are moderately stable
and readily isolated.10 We focused on the formation of
4-(2-chlorophenyl)morpholine 3a from N-chloromorpho-
line 1a0 and 2-(trimethylsilyl)phenyl triflate 2 to identify
optimal conditions for the proposed insertion reaction
(Table 1). Ina solvent screenemployingCsF asthe fluoride
anion source, MeCN proved to be the optimal solvent
(entry 1), leading to desired product 3a in 50% yield while
THF, 1,4-dioxane, toluene, and DMF were less effective.11
Increasing the temperature accelerated the reaction
(entries 2 and 3). In the subsequent studies where 60 °C
was chosen as optimal temperature, other fluoride sources
such as KF and TBAF (entries 4 and 5) were found to be
less efficient than CsF while the reaction performed in
lower concentration gave better reproducibility with a
comparable yield of 3a (entry 6 vs 3). Additional surveys
of the reaction stoichiometry (entries 7ꢀ9) revealed that
the instance with 1a0 as the limiting reagent, 1.5 equiv of
benzyne precursor 2, and 3.0 equiv of CsF afforded the
highest yield of 3a (entry 8). Based on these results, we next
looked into a one-pot protocol starting from amine 1a, as
elimination of the N-chloramine isolation step would be
attractive.12 We first treated amine 1a with N-chlorosuccin-
imide (NCS) to form N-chloromorpholine 1a0, which was
subsequently subjected to the insertion reaction with 2
(entry 10). Encouragingly, this one-pot protocol provided
the desired product 3a in 63% yield upon the complete
consumption of N-chloromorpholine.13
in a single operation. Arynes are one of the oldest, most
interesting, and useful reactive intermediates.6 Aryne
chemistry has proven extremely valuable for the synth-
esis of complex arene products, particularly evidenced
by remarkable advances in the past decade.7 Aryne
insertions,8 which allow for simultaneouslyfunctionalizing
two carbon atoms of an arene, are of high synthetic
significance and herald greater potentials of aryne inter-
mediates. However, aryne insertion into NꢀX bonds
remains unexplored, despite its promise in the synthesis
of valuable aminoarene derivatives. Considering the in-
stability of NꢀX bonds, we envision that mild reaction
conditions would be critical to minimize decomposition of
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With the developed one-pot insertion protocol, we ex-
amined the scope of this aryne insertion transformation
(Table 2). First, the reactions of benzyne with different
amines all delivered the ortho-chloroaminated arene pro-
ducts successfully (entries 2ꢀ6). A variety of functional
groups were tolerated under the reaction conditions,
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(13) Variations of these conditions (e.g., temperature, the equiva-
lence of each reagent) led to inferior results. See these results in the
Supporting Information.
Org. Lett., Vol. 15, No. 13, 2013
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