Organic Letters
Letter
arylboration.18 In this reaction, the Pd catalyst coordinates with
the directing group, controlling the regioselectivity of the
migratory insertion via formation of a five-membered pallada-
cycle.
a
Scheme 3. Optimization of the Reaction Conditions
Our strategy is based on a similar premise in that an amide
placed proximal to the alkene can be used to direct the migratory
insertion event. Preliminary investigation using previously
reported conditions10 revealed that the use of dimethylamide
4b allowed for formation of the syn diastereomer, thus
confirming the viability of our approach (Scheme 2). Evaluation
a
Scheme 2. Evaluation of Directing Groups
a
1
Yield refers to the yield of both diastereomers as determined by H
NMR analysis of the unpurified mixture with an internal standard.
b
c
Diastereomeric ratio at the indicated carbon. The reaction was run
with 10% NiCl2(DME), (Bpin)2 (4.0 equiv), base (3.0 equiv), and 4-
CIC6H4Br (2.0 equiv) at 50 °C.
the base from Na+ to K+ increased the diastereoselectivity
significantly without a substantial loss of yield, culminating in an
optimal set of conditions (Scheme 3, entry 11).
Next, the scope of the directed arylboration was investigated.
With respect to the alkene component, the standard substrate
(product 5) reacted smoothly (Scheme 4). Substituents at the α-
position of the amide were tolerated (product 6), albeit with
lower diastereoselectivity due to allylic strain with the amide.
When the α-substituent was constrained to a ring within the
amide, this strain was eliminated, and the high diastereose-
lectivity was restored (product 7). Additionally, trisubstituted
alkenes were tolerated and allowed for the formation of
quaternary carbons (products 8 and 9). Notably, these examples
represent the formation of densely substituted cyclopentanes. At
this point, the alkene scope is limited to cyclopentene
derivatives; cyclohexene-derived substrate 16 was not reactive,
but this is consistent with previous reports demonstrating that
cyclohexene is significantly less reactive than cyclopentene.9,10
The reaction was also tolerant of a variety of aryl bromides,
including electron-deficient (product 5), electron-rich (product
11), and sterically demanding (products 12 and 14) examples.
Additionally, the functional group tolerance was evaluated and
included tertiary amine and aniline derivatives (products 15 and
18, respectively). Heteroaryl bromides such as pyridine
(product 19), indole (product 17), and furan (product 20)
also functioned well in the reaction. Alkenylboration was also
achieved through the use of a vinyl bromide (product 21),
installing two easily derivatized functional groups in a single
transformation.
a
1
Yield refers to the yield of both diastereomers as determined by H
NMR analysis of the unpurified mixture with an internal standard.
of amides revealed that use of N-methyl-N-phenyl derivative 4e
led to an increase in diastereoselectivity favoring diastereomer 5,
as confirmed by X-ray crystallography. It is important to note
that the reaction of 4a resulted in the formation of the anti
diastereomer, presumably through a nondirected sterically
guided pathway.
After the feasibility of the directed arylboration was
established, the reaction conditions were optimized to favor
binding of the pendent amide to Ni. Since DMA can compete
with the pendent amide for coordination with Ni, it was omitted
from the reaction, resulting in an increase in diastereoselectivity
but a concomitant decrease in yield (Scheme 3, entry 3).
Improving the yield without loss of diastereoselectivity proved
to be a delicate balance of variables in the reaction conditions.
The yield of the reaction could be restored through the use of
toluene as the solvent instead of THF; however, the
diastereoselectivity was lowered. The yield was significantly
improved by the use of increased equivalents of reagents at a
higher temperature (Scheme 3, entry 6). Furthermore, in an
attempt to improve the diastereoselectivity of the reaction,
electronically (Scheme 3, entries 7 and 8) and sterically (Scheme
3, entries 9 and 10) modified directing groups were explored, but
no added benefit was found. Lastly, switching the counterion of
Furthermore, the reaction was performed on a gram scale and
worked with similar yield and selectivity as for the smaller-scale
reactions (Scheme 5A). To demonstrate the synthetic utility of
the products, the boronic ester and amide units of 5 were
functionalized through oxidation (22), homologation (24),
olefination (26), hydrolysis (23), and reduction (25) (Scheme
5B). Confirmation of the stereochemistry of 23 by X-ray
crystallography verified that epimerization of the α-stereogenic
613
Org. Lett. 2021, 23, 612−616
Lambright, Alison L.
