Preliminary molecular modeling based on
our previous computational work ( 19 )onthe
enantioselective borylation of 2-propylpyridine
predicted that a simple urea-pyridine conju-
gate with an ortho-phenylene linker connected
to one of the N atoms of urea and the 3-position
of the pyridine such asRLwould produce a
chemical space suitable for the binding of
aliphatic carboxylic acid derivatives that posi-
tioned one of theg-C–H bonds in proximity to
the Ir center (Fig. 1B). We then synthesizedRL
and found its exceptional utility as a recep-
tor ligand to create an enantioselectiveg-C–H
borylation catalyst.
Specifically, the reaction betweenN,N-
dibenzylhexanamide1a(0.3 mmol) and pinB–
Bpin (1 equiv) in the presence of 2,6-lutidine
additive (0.75 equiv) and an iridium cata-
lyst prepared in situ from [Ir(OMe)(cod)] 2
(1.5 mol %),L*(3 mol %), andRL(3.3 mol %)
in toluene (PhMe)/cyclopentyl methyl ether
(CPME) mixed solvent (PhMe/CPME 1:1, 2 ml)
at 25°C over 48 hours occurred with complete
substrate conversion and with exclusive site
selectivity(>99:1)attheremotepositiongto the
carbonyl group of the aliphatic chain to produce
alkylboronate2a[99%^1 H nuclear magnetic
resonance (NMR) yield]. Virtually perfectenantiocontrol was obtained as judged by high-
performance liquid chromatography (HPLC)
analysis of the corresponding secondary alco-
hol [(R)-3a, >99.9% enantiomeric excess (ee)]
(Fig. 2, entry 1) (see table S4 for solvent effects).
The reactivity was hampered and the enantio-
control was notably diminished by increasing
the reaction temperature from 25°C over a
range up to 80°C (Fig. 2, entries 1 to 4, no
side product was detected). The observed neg-
ative temperature–reactivity correlation is sup-
portive of the postulated substrate binding
through the urea-carbonyl hydrogen bond-
ing, which should be less favorable at higherReyeset al.,Science 369 , 970–974 (2020) 21 August 2020 3of5
Fig. 3. Substrate scope
of the enantioselec-
tiveg-methylene C–H
borylation and product
transformation.Reac-
tion conditions for
(A)to(D) Substrates
1b–y, 5a–d(0.30 mmol),
pinB–Bpin (1 equiv),
[Ir(OMe)(cod)] 2 (1.5 mol %),
L(3.0 mol %),RL
(3.3 mol %), PhMe/
CPME 1:1 (2 ml), 25°C,
48 hours. For the reactions
of1vand5a–d,the
reaction time was
56 hours. Yields are
those for the isolated
products (2b–h,3i–y,
6a–d). Conditions for the
oxidation reaction in the
case of tertiary amides:
NaBO 3 ·4H 2 O (3.0 equiv),
THF/H 2 O 1:1 (2 ml),
room temperature,
3hours.(A)Secondary
carboxamides, (B) ester
derivatives, (C) tertiary
amides, and (D) aliphatic
carboxylic acid deriva-
tives with different alka-
noyl groups. (E)Gram-
scale preparation of
(R)-2c(Ir-L:1mol%)
and its derivatizations.
DABCO, 1,4-diazabicyclo
[2.2.2]octane. NBS,
N-bromosuccinimide.
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