Journal of the American Chemical Society
Article
retard undesired boryl-substitution reactions. Notably, our
reaction can be applied to a variety of electrophiles including
gem-difluoro alkyl bromides, a monofluoro alkyl bromide, and
secondary and tertiary alkyl bromides, which cannot be
employed under any other hitherto reported 1,2-alkylbor-
ylation reaction conditions.22,23
Scheme 1. A Comparison of Methods for Copper(I)-
Catalyzed Intermolecular 1,2-Alkylborylation Reactions
RESULTS AND DISCUSSION
■
As a proof-of-concept, we selected α,α-difluoro alkyl bromide
1a as the alkyl electrophile; applying our previously reported
catalysts system, 1a did not furnish the corresponding boryl
substitution product.24,25 Surprisingly, the trial experiment
delivered the desired 1,2-alkylborylation product (4aa) in 13%
gas chromatography (GC) yield in the presence of CuCl/
PCy3, our efficient catalyst for the boryl substitution of alkyl
halides, under concomitant formation of unidentified by-
products (Scheme 2).24
a
Scheme 2. Initial Attempt of the 1,2-Alkylborylation
a
Conditions; 1a (0.1 mmol), 2a (0.4 mmol), 3 (0.12 mmol), CuCl
(0.005 mmol), PCy3 (0.005 mmol), K(O-t-Bu) (0.12 mmol), THF
(200 μL). The yield of 4aa was determined by GC analysis of the
crude reaction mixture with C13H28 as the internal standard.
This initial success prompted us to conduct an extensive
optimization study of the reaction conditions.32 We found that
4aa could be obtained in a 79% GC yield using a
[Cu(MeCN)4]BF4/IMes·HCl catalyst system with B2(pin)2,
K(O-t-Bu), and a catalytic amount of ZnBr2 as an additive in
1,4-dioxane/DMF (4/1, v/v) at 50 °C (Table 1, entry 1).
Using the optimized conditions, we then investigated several
other alkyl bromides to understand which electrophiles are
suitable for the intermolecular 1,2-alkylborylation (Table 1,
entries 2−5). The reaction with 1-adamantyl bromide (1b), a
tertiary alkyl bromide, also delivered the 1,2-alkylborylation
product in good yield, while the corresponding boryl-
substitution product (5) was not detected (Table 1, entry
2). These results indicate that the electronic effect and/or
steric repulsion play an essential role in preventing the boryl-
substitution reaction and facilitate the radical-relay mechanism
efficiently. Furthermore, we found that the intermolecular 1,2-
alkylborylation reactions of olefins with a monofluoro alkyl
bromide (1c) and a secondary alkyl bromide (1d) proceeded
when an excess of olefin was used (Table 1, entries 3 and 4).
The lower yields of these reactions relative to those with
difluoro or tertiary alkyl bromides are mainly due to the
competing inevitable boryl-substitution reactions. It should be
noted here that the intermolecular 1,2-alkylfunctionalizations
of olefins via a radical-relay mechanism with secondary alkyl
electrophiles are usually difficult to achieve due to competing
coupling reactions.7−14 In contrast, a primary alkyl bromide
(1e) predominantly furnished the boryl-substitution product,
and only trace amounts of the 1,2-alkylborylation product were
obtained (Table 1, entry 5).
cyclization was achieved in 2017.24 Despite this success, the
intermolecular counterpart has not yet been achieved due to
the difficulty in suppressing the direct coupling between the
borylcopper(I) intermediate and the carbon electrophile.
During related studies on the copper(I)-catalyzed borylation
of alkyl halides, we have encountered a problem where, despite
observing consumption of the starting materials, substrates
with electronically or sterically demanding substituents did not
afford the desired boryl substitution products. We hypothe-
sized that this outcome could be due to the boryl copper(II)
intermediate being inaccessible to the alkyl radical inter-
mediate on account of an electronic effect or steric repulsion.
Inspired by these results, we suspected that the reaction of an
unactivated olefin with bis(pinacolato)diboron and an
electronically or sterically demanding alkyl electrophile might
offer an alternative pathway to enable the intermolecular 1,2-
alkylborylation reaction. We speculated that this reaction could
proceed via a radical-relay strategy since the boryl substitution
reaction would be retarded using these electrophiles (Scheme
1B).25−27
Herein, we report the first example of an intermolecular 1,2-
alkylborylation of unactivated olefins via a radical-relay
strategy. The key to the success of this protocol is the use of
electronically or sterically demanding alkyl electrophiles to
We also evaluated the other reaction parameters under the
optimal conditions. Notably, the choice of ligand had a marked
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J. Am. Chem. Soc. 2021, 143, 5260−5268