Communication
lysts of note. Further, byproducts arising from benzyne forma-
tion, a common side reaction,[19] were not observed with ortho-
chloro substrates (19).
In an important observation, near perfect bromide/chloride
chemoselectivity at À228C (15 to 24) was obtained with diha-
logenated OA partners (see optimization table in the Support-
ing Information). Even when the bromide was sterically hin-
dered (16, 18), it was coupled preferentially over the chloride.
Previously, the chemoselective[1,4,20] and sequential[21] couplings
of bromo-chloro-arenes were achieved by changing solvent
polarity, rate of transmetallation (TM) of the nucleophiles, or
simply by using less reactive catalysts. For example, Watson
and co-workers reported two interesting articles on the one-
pot sequential Suzuki–Miyaura couplings of bromo-chloro-
arenes controlling the rate of TM of the organoboron re-
agents.[21a,b] Very recently, Schoenebeck and co-workers pre-
sented the one-pot sequential Negishi couplings of bromo-
chloro-arenes by sequential addition of aryl/alkyl zinc reagents
and changing the solvent polarity.[21c] The catalytic turnover
from C3 at À628C shows that it is one of the most reactive
catalysts yet reported for this transformation.
With this in mind, we envisioned a one-pot methodology in
which a single catalyst would be capable of coupling multiple
nucleophiles in a chemoselective fashion by using temperature
as the selectivity trigger. This methodology would allow diver-
gent synthesis to be achieved in an efficient manner, providing
a powerful tool for synthesis. Methodology for the sequential
coupling of two sp2 hybridized organometallic reagents with a
dihalide electrophile is known, but a general cross-coupling
procedure in which one of the coupling partners is a sp3 hy-
bridized nucleophile is less prevalent.[21d,f] Small alkyl frag-
ments, and in particular secondary (branched) centers, are cru-
cial for the development of potent biomedically active com-
pounds that bind with high selectivity to their protein tar-
gets.[22] The importance of such motifs in the structure of elec-
tronic materials is also well demonstrated.[23] Therefore, the
development of an operationally simple, one-pot procedure to
readily install such alkyl substituents on (hetero)aromatic core
structures is highly desirable. Organolithium reagents coupled
smoothly at À228C with bromo/chloro aromatics providing in-
termediates to which were added the reactants for Suzuki–
Miyaura (25), Negishi (26, 28), Murahashi[24] (27, 29, 30) and
Scheme 3. One-pot sequential approach to divergent synthesis of function-
alized molecules. Overall yield of isolated products following two-step pro-
cess after column chromatography are reported in brackets. Additional reac-
tions are reported in the Supporting Information. Conditions for second cou-
pling: [a] ArB(OH)2 (1.5 equiv), NaOMe (3 equiv), THF (3 mL), 758C, 18 h.
[b] ArZnBr (1.5 equiv) 238C, 18 h. [c] ArLi (1.5 equiv) dropwise, 1 h, 408C.
[d] First step at 08C; second step 1.5 equiv ArMgCl, 238C, 18 h. [e] Ar-NH2 or
Ar-NHMe (1.2 equiv), KOtBu (1.5 equiv), 238C, 18 h. [f] Ar-NH2 (1.2 equiv),
Cs2CO3 (3 equiv), 808C, 18 h. [g] 1.5 equiv KOtBu, 1.5 equiv ArNH2, 608C,
18 h. [h] Ar-SH (1.2 equiv), KOtBu (2 equiv), 808C, 18 h. [i] Ar-SH (1.2 equiv),
KOtBu (2 equiv), 238C, 18 h.
It has been proposed by Larrosa et al. that following one
catalytic cycle with dihaloarenes that electron-rich Pd-PEPPSI-
IPr (C1) undergoes OA with the remaining halide site faster
than the catalyst can diffuse away from the mono cross-cou-
pling product, which accounts for why they observed only di-
coupling.[25] Indeed, rapid addition of nBuLi to naphthyl bro-
mide and C3 followed by the addition of methanol as quickly
as possible thereafter saw full conversion to 1, which worked
equally well on a 1-gram scale (Scheme 4). The process seems
general as deactivated OA partners (to give 12) and heterocy-
cles (43) also work fine. Finally, a telescoped, Murahashi/amina-
tion sequence like those in Scheme 3 worked perfectly well by
using the one-shot alkyl-lithium addition method producing
44 and 45 in excellent yield.
Kumada–Tamao–Corriu
(31)
cross-coupling
procedures
(Scheme 3). Not limited to carbon nucleophiles, amine aryla-
tion (32–39) and sulfination (40–42) reactions also proceeded
well to give highly functionalized, advanced building blocks.
Although the methodology developed above represents an
advancement for cross-coupling, Murahashi coupling,[24a] it is
still thwarted by the perceived drawback for the necessity of
syringe-pump addition.[7] Gradual charging of the reagent miti-
gates fast organolithium-related catalyst decomposition. What
would be required to make the more-desirable, single-shot in-
jection of the nucleophile possible is for catalysis to be so
rapid that decomposition (presuming that it occurs) cannot
complete with the desired pathway.[24b] Key would be a catalyst
system capable of undergoing OA at near diffusion-limiting
rates.
In conclusion, the unprecedented coupling of organolithium
reagents at cryogenic temperatures (as low as À788C) has
Chem. Eur. J. 2019, 25, 1 – 6
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