Organic Letters
Letter
Scheme 1. Selective Cross-dehydrogenative C(sp3)−H
Arylation with Inert Arenes
Scheme 2. Screening of Auxiliaries for Selective C(sp3)−H
a
Bond Arylation with Toluene
a
Reaction conditions: DG X (0.1 mmol), Pd(OAc)2 (0.01 mmol),
NFSI (0.2 mmol), AgNO3 (0.1 mmol), toluene (1.0 mL), 65 °C, 24
b
h, GC−MS yields. DG X (0.1 mmol), Pd(OAc)2 (0.01 mmol), NFSI
(0.15 mmol), AgNO3 (0.02 mmol), toluene (1.0 mL), 90 °C, 24 h.
(2a−j). Diarylation was observed in the reaction of
isopropanol derived substrate (2d). The arylation of simple
ethanol-derived substrate also took place in good yield (2g).
Notably, the arylation only occurred at the primary methyl C−
H bond, leaving the reactive benzylic C−H bond or C−H
bond that adjacent to heteroatoms intact (2h−j).
Next, various mono- or multisubstituted simple arenes were
further investigated (2k−t). Excellent arylation/fluorination
selectivity (up to 51:1) and para-selectivity (up to 50:1) were
both observed in most cases. Notably, cross-coupling reactions
took place only at the more nucleophilic and less hindered site
of the aromatic rings (2r−t). For instance, β-arylation with 2-
chloro-anisole selectively occurred at the para position of
methoxy group, which was further confirmed by the X-ray
analysis (2t-Ar). Attempt to reduce the loading of arenes was
also conducted. C(sp3)−H arylation with 20 equiv of arenes
under neat condition gave comparable yields but lower
chemoselectivitity (the ratio of arylation vs fluorination was
up to 8:1). Further reducing the arene loading (5−10 equiv)
led the decrease of yield and selectivity (see Table S7 for
details).
the selective C(sp3)−H bond fluorination of alcohols.14 The
versatile and modular-accessible pyruvamide directing groups
enabled the selective C−F bond reductive elimination over
other competing side reactions. Encouraged by the previous
reports, we envisaged that a selective dehydrogenative C(sp3)−
H arylation of alcohols with simple aromatic C(sp2)−H bonds
might be accessible with a proper pyruvamide directing group
(Scheme 1d).15
Given the sluggish C−F bond formation, NFSI (N-
fluorobenzenesulfonimide) has been used as a so-called
“bystanding” oxidant in the high-valent Pd(IV) involved
C(sp2)−H arylation, which exhibits good site-selectivity even
with the monosubstituted aromatics.16 Hence, at the outset of
this project, a masked alcohol bearing N-pentafluorophenyl
pyruvamide derived bidentate auxiliary was treated with
Pd(OAc)2 and NFSI in toluene (Scheme 2). The desired
C(sp3)−H arylation with toluene was observed in moderate
53% yield along with a good arylation/fluorination selectivity
(9:1) (DG 1). Further screening of the auxiliaries showcased
that N-(3,5- ditrifluoromethylphenyl)pyruvamide oxime could
give an even better chemoselectivity (33% yield, 12:1) (DG 4).
In contrast, a neutral L,L-type bidentate auxiliary only provided
poor selectivity (DG 6). Improved yield and selectivity were
both obtained by further fine-tuning of the reaction conditions
(80% yield, 20:1; see the SI for details, Table S6) (DG 4).
Moreover, the excellent para-selectivity was further confirmed
by the X-ray crystal structure of product 2a-Ar (Scheme 3).
With the optimized conditions in hand, the scope of the
CDC strategy was investigated (Scheme 3). Generally,
different masked secondary alcohols underwent β-arylation
with toluene in good to excellent chemo- and regio-selectivities
Encouraged by challenging intermolecular arylation with
simple arenes, we envisaged that an intramolecular CDC
reaction might facilitate the second aromatic C−H bond
activation and provide a modular access toward valuable
tetrahydronaphthalen-2-ols or benzopyran-3-ols in an atom-
economical fashion. Indeed, these benzofused scaffolds are
important and ubiquitous in various bioactive compounds such
as corynoline, deN-corynoline, epicatechin, and cromakalim,
etc. (Scheme 1c). To our delight, with slight modification of
the intermolecular CDC reaction conditions, the desired
cyclization product 4a was isolated in 87% yield from the
cyclization of masked 4-phenylbutan-2-ol 3a using (CH2Cl)2
as the solvent. Notably, no fluorination was observed in this
intramolecular CDC process under the optimized condition
Then, the scope of intramolecular CDC cyclization was
extensively investigated. As shown in Scheme 4, CDC
B
Org. Lett. XXXX, XXX, XXX−XXX