Nature Chemistry
Articles
Received: 13 March 2019; Accepted: 29 January 2020;
species might afford an aryl hypoiodite intermediate 25, which
might give o-QM via the reductive elimination of ammonium
iodide directly or after dissociation49 to the phenoxenium cation 26.
The β-deprotonation process might be helped by the base species
(R4N+Y–, Y=ArO, RO, and so on) generated in situ catalytically.
To gain further insight into the mechanism of the generation of
o-QMs, we performed kinetic studies using the oxidative dimer-
ization of 1a as a model reaction (see Supplementary Figs. 4–6).
The reaction rate was found to have a first-order dependence on
the concentration of catalyst 6d and a zero-order dependence on
both substrate 1a and hydrogen peroxide. These results suggest that
reductive elimination might be the rate-determining step in the
catalytic cycle (Fig. 6a). Finally, the secondary kinetic isotope effect
(KIE)50 for the oxidative dimerization of 1a and 1a-d3 in separate
vessels based on the initial reaction rates was observed to be 1.8
(Fig. 6b), which suggests that β-deprotonation might proceed after
dissociation to phenoxenium 26 (Fig. 6a). Therefore, electrostatic
or hydrogen-bonding interactions51 between the leaving iodide and
the ammonium cation centre or acidic α-hydrogen atoms of the
highly reactive catalyst 6d, respectively, might enhance the reactiv-
ity of the dissociative reductive elimination step.
The highly reactive o-QMs generated in situ would then react
rapidly with a suitable nucleophile to give the corresponding cou-
pling products. The ammonium cation of the catalyst might not
bind strongly enough to the pro-chiral o-QMs to induce stere-
oselectivity during this process. Indeed, no asymmetric induction
was encountered with the use of chiral ammonium iodides for the
oxidative cycloaddition or electrocyclization reactions. On the
other hand, some attractive interactions would be expected with
the anionic nucleophiles51, which enable the asymmetric induc-
tion during the conjugate addition of o-QMs. Intramolecular
oxa-conjugate cyclization of 17 and spiroepoxidation of 7q in the
presence of chiral ammonium iodides 6f20 or 6g39, respectively,
gave the corresponding products 18 and 19g with moderate
enantioselectivity (Fig. 6c). These preliminary results revealed
the feasibility of the use of this ammonium hypoiodite cataly-
sis for the enantioselective oxidative coupling reaction through
o-QM intermediates.
In summary, we have developed a transition-metal-free catalytic
oxidative generation of o-QMs using hypoiodite catalysis through
the oxidation of ortho-alkylarenols and applied o-QMs as transient
reactive intermediates to tandem reactions. Inexpensive tetrabutyl-
or tetramethylammonium iodides or sodium iodide could be used
as a catalyst. Moreover, to induce higher reactivity, a new structur-
ally compact quinuclidine-derived quaternary ammonium iodide
catalyst has also been designed. A mechanistic investigation sug-
gests that the rate-determining step of the present catalysis might
be the dissociative reductive elimination of iodide from the aryl
hypoiodite intermediate. This method for the chemoselective gen-
eration of o-QMs is superior to previous methods with respect to
not only environmental issues but also the wider scope, especially
with respect to coupling partners, and could be applied to various
oxidative tandem reactions such as inter- or intramolecular [4+2]
cycloaddition (including self-dimerization or trimerization and
enantioselective cycloaddition), oxa-6π-electrocyclization, inter- or
intramolecular conjugate addition with nitrogen or oxygen nucleo-
philes and spiroepoxidation. Strikingly, several chemoselective
divergent oxidative couplings could be achieved by simply changing
the reaction conditions.
Published: xx xx xxxx
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