with a good yield but moderate selectivity
(8.1:1). Phenylsilane (1q) reacted with high yield
and highmetaselectivity (18:1). A mesitylene
substituent (1r) decreased both yield and se-
lectivity, possibly because of unproductive inter-
action with the roof substituents on the ligand.
Electron-deficient monosubstituted arenes
such as pivalophenone (1s) and diethyl phenyl-
phosphonate (1t) reacted with moderatemeta
selectivity. The electron-withdrawing group in
these substrates accelerates the oxidative addi-
tion of theparaC–H bond, but the roof ligand
overrides the electronic effect and enhances
metaselectivity. An unsymmetricallyortho-
disubstituted arene (1u) reacted with mod-
erate selectivity at the C–H bondmetato the
bulkier group, which shows that the ligand
can differentiate between the size of the two
groups. Several less successful substrates are
shown in fig. S1.
Late-stage functionalization of complex mole-
cules is important for medicinal chemistry
because it enables the streamlined creation
of new chemical space for the development of
new drugs. We tested our reaction for several
commercially available drug molecules contain-
ing various functionalities. Caramiphen (1v), an
anticholinergic drug used for the treatment of
Parkinson’s disease, wasmeta-borylated with
high yield and selectivity (20:1). Borylation of
this compound at theparaposition (para/
meta= 5.7:1) was previously reported ( 13 ).
Pirfenidone (1w), anN-phenylpyridinone de-
rivative used for the treatment of idiopathic
pulmonary fibrosis, was borylated in low yield
but with highmetaselectivity. Although thereis interest in the development of pirfenidone
derivatives to increase potency and reduce side
effects,theonlyreport( 33 ) on derivatives func-
tionalized at the phenyl group required multiple
steps, using the Ullmann coupling of the NH
precursor withpara-substituted aryl bromides.
Methylphenidate is a stimulant drug used
mostly for the treatment of attention deficit–
hyperactivity disorder. After protection of the
piperidine’s nitrogen,1xwas borylated with
high yield andmetaselectivity [2x, 74%;3x,
18%;4x, 8% as determined using^1 H nuclear
magnetic resonance (NMR) spectroscopy,2x
isolated in 50% yield]. The structure of product
2xwas confirmed by x-ray crystallography (fig.
S4). Medicinally relevant compounds2vto2x
could be isolated as the analytically puremeta
isomer by gel permeation chromatography.660 11 FEBRUARY 2022•VOL 375 ISSUE 6581 science.orgSCIENCE
Fig. 2. Key structural features of the
ligand.Reactions were conducted with
tert-butylbenzene (1a, 0.20 mmol), B 2 pin 2
(0.22 mmol), [IrOMe(cod)] 2 (2 mol%),
and ligand (4 mol%) in dioxane (1.5 ml)
at 90°C for 16 hours. The yield and
selectivity were determined using gas
chromatography in the presence of
hexadecane as an internal standard, after
calibration (see supplementary materials).
Ph, phenyl. *HBpin (0.40 mmol) and
dioxane (2.0 ml) were used.
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