Journal of the American Chemical Society
Communication
underwent C−H activation at the para position, regardless of
electronics, with a single exceptionanisole. Metalation on
anisole resulted in metalacycle formation with concomitant dual
Of prime importance is the influence of ancillary ligand L on
the success of the carboannulative process. Control experiments
under identical conditions with the exclusion of DMSO did not
produce any detectable annulation product. On this basis, we
undertook a substantive mechanistic investigation that we here
reveal is fully consistent with the inability of moderate-to-
strongly binding ligands to dissociate from iridium(III), a
process required during a key step in the catalytic cycle. This
establishes the loosely bound sulfoxides as privileged coligands
that enable facile undirected C−H bond activation.
2
3
C(sp )−H and C(sp )−H bond activation. We speculated that
this metalacycle could be intercepted by an alkyne coupling
partner leading to a productive carbocarbation (Scheme 1c).
Herein, we report the design and development of a catalytic
system that enables the unprecedented double C−H
functionalization of anisoles. This iridium-catalyzed reaction is
initiated by a nonchelate-assisted C−H bond cleavage, a
process that is shown to rely on the nature of the ancillary
ligand used. Appealingly, the sequential C−H activations
Anisole 1a is metalated quantitatively when heated with
stoichiometric amounts of [Cp*IrCl ] , DMSO, and 1-
2
2
21−23
generate chromenes
containing a monofluoroalkene side
AdCO Cs (Figure 1a). Omission of any one of these
2
chain, a peptide bond bioisostere commonly applied in
components does not lead to product. The structure of the
24
medicinal chemistry.
resultant DMSO-bound metalacycle met-1a was established
26
To begin our investigation, we examined the activation of 4-
unequivocally by X-ray diffractometry. Although remarkably
stable at ambient temperature, met-1a recovers its catalytic
activity when heated together with 1a and 2a under the
standard reaction conditions. Indeed, the yields of product 3aa
are similar from reactions catalyzed by either met-1a (52%) or
an equimolar mixture of [Cp*IrCl ] and DMSO (57%, Table
(
trifluoromethyl)anisole (1a). Ison’s seminal work was
17
performed with anisole as solvent; we settled on 5.0 equiv
relative to the coupling partner in hydrocarbon solvents as a
more synthetically tractable solution. In an initial screen of
potential coupling partners, we identified gem-difluoroalkynes
2
2
(
2) as suitable substrates for oxidative annulation, presumably
1, entry 2). In an attempt to shed light on alkyne insertion into
met-1a, we anticipated that 3-hexyne (4) could trap the relevant
Ir(III) intermediate because it lacks the reactive gem-difluoro-
methylene group. Gratifyingly, met-1a inserts 4 cleanly under
by virtue of their mild oxidizing potential combined with high
thermal stability. Disappointingly, however, heating 1a and 2a
together with catalytic amounts of η -pentamethylcyclopenta-
2
5
5
3
dienyl iridium(III) complex [Cp*IrCl ] (Ir1), DMSO (L1),
thermal conditions (Figure 1b), affording an Ir(III)-η -allyl
2
2
and excess CsOAc leads to trace amounts of the desired
complex (5) that was also characterized by X-ray crystallog-
26
26
chromene product (3aa). We speculated that this was due to
raphy. These experiments are fully consistent with met-1a
27
inactivation of the iridium(III) catalyst by fluoride. Several
fluoride ion scavengers were tested, with the target product
observed in small amounts (12% yield) when employing
being an off-cycle precursor to a reactive intermediate.
Further insight was gained from an examination of
isotopically labeled substrates. When subjecting deuterated
anisole 1a-d8 to the optimized catalytic conditions using
buffered 1-adamantanecarboxylic acid as the proton source,
considerable deuterium leaching is observed at the ortho and
para positions of the arene ring (83% and 87% of deuterium
retention, respectively) (Figure 1c). This indicates that arene
26
trimethylsilyl acetate (Si1) as an additive. The use of a
Cu(OAc) /O system for iridium reoxidation results in an
2
2
increased yield of 25% signaling catalyst turnover (Table 1,
Table 1. Reaction Development
2
C(sp )−H activation is reversible under the present reaction
conditions. Furthermore, based on a competition experiment
between partially deuterated metalacycle met-1b-d and non-
deuterated bromoanisole 1o, it was demonstrated that
deuterium atoms do not crossover between the two molecules
(
Figure 1d). Additionally, a notable kinetic isotope effect (KIE)
of 2.5 is obtained from a series of competition experiments
between protio-anisole (1b) and deuterio-anisole (1b-d3)
(
Figure 1e). Taken together, the above experimental
3
observations imply that C(sp )−H activation at the methoxy
group of anisole is irreversible and turnover-limiting.
An influence of the steric bulk of the carboxylate base on the
regioselectivity of anisole metalation is observed, with more
hindered bases (1-AdCO Cs > PivOCs > AcOCs) leading to a
2
higher preference for cyclometalation over para-metalation
aDetermined by 19F-NMR with 1,3,5-trifluorobenzene standard.
(
Figure 1f). In sharp contrast, when performed catalytically, the
reaction affords exclusively the doubly C−H functionalized
product even with a smaller base such as CsOAc (Table 1,
entry 1). These results are fully consistent with a nonchelate-
assisted C−H activation pathway, where the regioselectivity of
entry 1). Among other silanes tested, dimethyl diacetoxysilane
(Si2) is optimal and, in combination with cesium adamantane-
2
1
-carboxylate (1-AdCO Cs), affords a 57% yield of 3aa (entry
the initial C(sp )−H bond cleavage is driven solely by the
2
28
3
29
2). In addition, a significant impact of Cp-ligand electronics
irreversibility of subsequent C(sp )−H activation.
on reaction outcome is observed, with more electron-deficient
Ir2 and Ir3 leading to higher yields (entries 3, 4).
Correspondingly, a combination of catalyst Ir3 bearing two p-
Taken together, our mechanistic data are supportive of the
following catalytic cycle (Figure 1g). The active catalyst is
presumably the coordinatively unsaturated, cationic mono-
acetato Cp*Ir(III) fragment I that is generated from
26
CF substituted phenyl rings with cyclic sulfoxide L2 affords
3
2
chromene 3aa in a respectable 75% yield (entry 5).
[Cp*IrCl ] , DMSO, and CsOAc. Arene C(sp )−H activation
2
2
B
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX