Organic Letters
Letter
of 5 mol % [PdCl(C H )] , 10 mol % 2-(dicyclohexylphos-
Intermolecular Reductive Heck Reaction
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5
2
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f
a
phino)-1-phenyl-1H-pyrrole (cataCXiumPCy), LiOAc,
NCCH CO H, H O, and 2,3-butanediol was found to
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2
2
promote the reaction at 130 °C, affording N-(quinolin-8-yl)-
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previously discovered that the hydrogen-bonding effect could
facilitate halide dissociation from neutral arylpalladium halide
4
,9
complexes, various hydrogen-bond donors (H-BDs) includ-
cyanoacetic acid, and 2,3-butanediol was identified to
efficiently generate the putative cationic aryl−Pd(II) complex
in this reductive Heck reaction. Silver salts acting as halide
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scavengers led to only a trace amount of the desired adduct.
We suspected that the silver source might oxidize the active
0
4
Pd catalysts. For other reaction condition optimizations, see
Under the optimal reaction conditions, we first investigated
the scope of organohalides (Table 1). As expected, aryl
substituents carrying either electron-donating or electron-
withdrawing groups performed well (P1−P7). Notably,
sensitive functional groups such as SMe, OH, N(Me) ,
2
a
Reactions were run on a 0.3 mmol scale. Percentages represent
isolated yields.
SO Me, and NO , which were problematic in our previous
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method, were found to be compatible in this practical
protocol (P8−P12). The effect of steric hindrance also
remained minimal (P13−P20). Several sterically hindered
polyaromatic bromides worked well, too (P21−P24). Mean-
while, an array of fluoro-containing aryl bromides was explored
our approach (P89−P92). Moreover, strong sterically
hindered alkyl-substituted intenal alkenes bearing Bu, Cy,
and long-chain alkenyl groups proceeded well for the first time
t
(
P25−P44) due to the wide existence of fluoro-substituted
(
P93−P95). A high yield of product (P94) also indicated that
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aryl groups in pharmaceuticals and natural products. Diverse
functional groups including F, CF , OTf, OCF , and SCF
the Z- and E-configured internal alkenes performed similarly
via the directing-group-controlled five-membered palladacycle.
Encouraged by the aforementioned extensive substrate scope
of this regioselective palladacycle protocol, we attempted to
assess the potential limitations of the alkene scope in the δ-
arylation of phenyl bromide (Table 3) because only
unactivated terminal alkenes showed moderate reactivity in
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3
3
were generally well-tolerated in different positions of the aryl
group. Moreover, this practical process could also be applied to
most major families of heterocycles including quinolines,
pyridine, indoles, benzofurans, dibenzofuran, thiophene,
bithiophene, benzothiophenes, benzothiazole, and carbazoles
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(
P45−P61). Remarkably, various vinyl electrophiles per-
our previous coupling of aryl triflates. As expected, various
formed well for the first time (P62−P67), and the relevant
tethered alkenes were obtained in good yield. While vinyl
bromide (S3) was used, debenzylation, followed by aromatiza-
tion, occurred after the intermolecular reductive Heck
reaction. Surprisingly, low-activity aryl chlorides could also
be successfully applied in our strategy, and moderate to good
yields of the corresponding products were afforded with
complete anti-Markovnikov selectivity (P68−P75). Notably,
strong sterically hindered substrates carrying an ortho group
and heteroaryl chlorides also performed well (P76−P79). In
summary, this practical protocol has successfully extended the
aryl electrophile to complex aryl groups, heterocycles, vinyl
groups, and even aryl chlorides, which could not be realized in
our previous method of aryl triflates.
terminal alkenes bearing an alkyl group at either the α- or the
β-position of the amide performed well (P96−P103). The
observation of stereoretentive products (P104, P105) revealed
that this coupling process was stereoretentive during the alkyl
palladacycle formation, which is consistent with geometrical
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data in the previous cationic reaction of aryl triflates. These
results might also indicate a possible cationic pathway after the
halide dissociation step. Notably, the disubstituted terminal
alkene was first well-tolerated (P106). Much to our
gratification, an array of challenging internal alkenes proceeded
well for the first time (P107−P111), and a moderate to
excellent yield of the exclusive δ-tertiary carbon center adduct
was obtained, consistent with the relative steric effect of distal
alkyl substituents. Remarkably, several more sterically hindered
trisubstituted internal alkenes were tested (P112−P115), and
diverse diarylmethine derivatives carrying branch alkyl chains
were efficiently synthesized. In summary, this general and
practical method is a powerful complementary approach to the
reductive Heck reaction of unactivated alkenes.
We next evaluated various unactivated aliphatic alkenes in
the γ-selective reductive Heck reaction of phenyl bromide
(Table 2). Both terminal and internal nonconjugated alkenes
participated well to form the linear and branch arylated
products in excellent yield and with exclusive regioselectivity,
respectively (P80−P88). Remarkably, although the diary-
lmethine core is a common motif in biologically active
A multigram scale reaction was conducted to demonstrate
the practicality of this methodology (Scheme 1, eq 1). Product
bearing a triflate group (P33) was afforded in 62% yield,
providing an opportunity to further functionalize this obtained
adduct. For example, our reported reductive Heck reaction of
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compounds, an efficient synthetic strategy is still rare so
far. Either symmetric or asymmetric diarylmethine derivatives
could be efficiently obtained from styrenyl internal alkenes in
C
Org. Lett. XXXX, XXX, XXX−XXX