Angewandte
Communications
Chemie
(e.g. more sterically hindered examples or those
bearing highly reactive functional groups), a slower
addition (over a 3–5 min interval) of the organome-
tallic coupling partner proved advantageous to ach-
ieve higher yields, regardless of whether the reaction
was performed in the presence or absence of air.
With these excellent selectivities proven, we
subsequently tested this methodology for its potential
in large-scale applications. Addition of n-butylzinc
chloride to 1 g of 2-bromo-4-chlorophenyl triflate
(2a), along with 1 mol% of the PdI catalyst 1 under
otherwise identical open-flask reaction conditions,
À
yielded the C Br coupling product (4a) in 91% yield
in 5 min. Thus, these coupling reactions are also
equally selective and rapid under reduced catalyst
loadings and significantly larger scales. As such, our
methodology allows for fully predictable, robust and
À
substrate-independent C Br alkylation under highly
practical conditions.
Having demonstrated the exclusive bromo-selec-
À
À
tivity in competition with C OTf and C Cl sites, we
next investigated the general synthetic applicability
of this methodology for less activated arenes con-
taining only a single coupling site along with addi-
tional functional groups (Scheme 2). Heterocycles as
well as electrophilic functional groups (i.e. aldehyde
6e, nitriles 6k and 6s, ketones 6d, 6p, 6q, ester 6j)
are well tolerated. The reaction could also be
performed in the presence of nitro (6k), azido (6i)
functionalities.[17] Also boronic acid esters (i.e. BPin,
6c, 6l, and 6m), which can enable further orthogonal
coupling reactions and hence molecular diversity.
In terms of the scope of organometallic reagents
a variety of alkylzinc, as well as some alkylmagnesium
coupling partners could be utilized. Alkyl groups,
both with and without b-hydrogen atoms, all proved
compatible and underwent smooth Csp2–Csp3 cou-
plings (Scheme 2). Methylation (6a) proceeded most
efficiently under Kumada conditions. A range of
secondary alkyl zinc and magnesium reagents could
also be coupled efficiently. The desired products were
obtained in good yields for both acyclic (i-Pr, sec-butyl) as
well as cyclic (cyclopropyl, -pentyl, and -hexyl) alkyl groups.
Products arising from isomerization of the secondary alkyl
moiety were detected either in trace amounts (ꢀ 3% with
6m) or not at all (6l, 6p,q), and as such are competitive with
the current state-of-the-art.[4a–f]
To shed light on the potential mechanism of the trans-
formation and the origins of exclusive bromo-selectivity, we
conducted computational studies and examined the predicted
À
Scheme 2. Scope of C Br alkylation and functional group tolerance. Reaction
conditions: 2 (0.4 mmol), R-ZnX 3 (0.8 mmol in THF, prepared from 0.8 mmol
of R-MgX and 0.84 mmol of ZnCl2), 1 (0.01 mmol), toluene (1.5 mL), open flask,
RT, 5 min.[18] [a] Using R-MgX as 3. [b] 3 was added drop-wise. [c] Alkyl-ZnX was
prepared from Alkyl-X using Mg, LiCl and ZnCl2. See Supporting Information for
details. [d] 0.6 mmol of 3. [e] 0.72 mmol of 3. [f] 1.2 mmol of 3.
I
À
bridged Pd dimer, which indicated a clear C Br addition
À
À
preference. Both C Cl and C OTf are predicted to be
significantly disfavored (by DDG° = 5.8 and 2.8 kcalmolÀ1).
Alternatively, Pd0PtBu3 may be active and our computations
°
À
suggest preferential C Br addition (by DDG = 4.4 and
8.3 kcalmolÀ1 for Cl and OTf). Overall, these data suggest
0
I
I
À
that both Pd -based and Pd Pd -based reactivities are con-
sistent with the observed C Br selectivity. The NHC and
À
CPhos systems (as presented in Figure 2) are also generally
presumed to form mono-ligated active Pd0 species.[11] We also
calculated the predicted selectivities for these cases. Interest-
À
À
À
site-selectivity for C Br versus C Cl versus C OTf as
a function of active species.[19] The dinuclear PdI dimers may
either react directly with aryl halides or act as a precursor for
monophosphine Pd0. In short, the precise mode of reactivity is
highly dependent on whether the coupling partner can
function as a bridging unit in the dinuclear entity.[13,20] For
related dinuclear NiI complexes, there has been very recent
evidence that carbon-based bridges may in fact be possible.[21]
We calculated the predicted selectivities for an n-propyl-
ingly, these Pd0L1 species also show a clear preference for
°
À
oxidative addition at C Br (by DDG = 5.6 and 7.8 kcal
À1
À
À
mol , respectively, for C Cl and C OTf with L = IPent, and
3.0 and 9.5 kcalmolÀ1 with L = CPhos). These data contrast
the observed lack of selectivities and point toward more
complex reactivity scenarios. For example, there could be
alternative reactive species, or oxidative addition may not be
Angew. Chem. Int. Ed. 2017, 56, 1 – 6
ꢀ 2017 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3
These are not the final page numbers!