Pd-Catalyzed reductive heck reaction of olefins with aryl bromides for Csp2-Csp3 bond formation

Article abstract of DOI:10.1039/c8cc02571a

We developed a Pd-catalyzed intermolecular reductive Heck reaction to construct Csp²-Csp³ bonds between aryl bromides and olefins. Various styrene derivatives, acyclic and cyclic alkenes, were well tolerated to couple with varied aryl bromides in linear selectivity. Kinetic and deuterium labeling experiments suggested that i-PrOH provides a hydride through β-H elimination.

Full text of DOI:10.1039/c8cc02571a

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Pd-Catalyzed Reductive Heck Reaction of Olefins with Aryl
Bromides for Csp2-Csp3 Bond Formation
Liqun Jin, *a,b Jiaxia Qian,a Nan Sun,a Baoxiang Hu,a Zhenlu Shen,a and Xinquan Hu *a,b
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
We developed
a Pd-catalyzed intermolecular reductive Heck less studied, except for the one utilizing special cyclic and
reaction to construct Csp2-Csp3 bonds between aryl bromides and strained olefins as ideal substrates,8 such as norbornene
olefins. Various styrene derivatives, acyclic and cyclic alkenes, were derivatives.9 Second, olefins with electron withdrawing groups,
well tolerated to couple with varied aryl bromides in linear such as the most commonly used conjugated enones,10 were
selectivity. Kinetic and deuterium labeling experiments suggested employed to react with Ar-Pd-X species generated in situ from
that i-PrOH provide a hydride through b-H elimination.
reaction mixtures. Third, in view of the regioselectivity, 1,2-
insertion or 2,1-insertion leading to the linear or branch desired
product, respectively, is also problematic while employing
inactivated olefins.11 Thus, it is of great importance to develop
a new catalytic system that exhibits wider tolerance for simple
olefins in a regioselective manner. In addition, the commonly
used reductants are formates/bases combination performing as
the hydride donor. VꢀŒÇ ŒꢀꢁꢀvšoÇU bꢂlꢂ}[• ꢂvꢃ .µꢁZÁꢂoꢃ[•
Pd-catalyzed Heck reactions are one of the most efficient and
powerful tools for construction of structurally sophisticated
alkenes, which have been widely applied in modern organic
synthesis.1 Such transformations generally involve coupling of
olefins, the alkenyl source, with aryl or vinyl electrophiles.
Mechanistically, the syn migratory insertion of olefin into Ar-Pd
bond and the subsequent b-H elimination are considered to be
the key elementary steps in the whole catalytic cycle.2 It is,
groups independently employed
a Pd/Cu/Si-H synergistic
catalysis in these rH transformations, in which branch rH
products were obtained when vinylarenes were utilized,12 while
a Ni/silane system was reported by Liu13 and Zhu14. Moreover,
Zhu and coworkers found a Pd/H2O system for enantioselective
rH reactions.15 Nevertheless, simple reductive systems are still
worthy to develop.
however, inescapable that the migratory insertion delivers a s-
Pd-alkyl intermediate. The interception of the -Pd-alkyl
s
species as the dominant quenching step leads to a Csp3-
centered compound but this transformation remains
challenging.3 In addition, directly utilizing olefins, which are
extensive, stable, inexpensive and of great diversity, as the Csp3
synthons is more synthetically practical and attractive,
compared to conventional alkylmetallic reagents or alkyl
halides.4
In the present work, we report a Pd-catalyzed rH reaction of
olefins with aryl bromides in an intermolecular fashion. This
reaction provides an efficient strategy for construction of Csp2-
Csp3 bonds with linear selectivity. The bidentate geometry-
constrained iminopyridyl (CImPy) ligand plays an important role
in stabilization of the catalytically active palladium center.
Reductive Heck (rH) reactions, initially disclosed by Cacchi
and coworkers, referred to the conjugate addition of Ar-Pd-X to
olefins and then reductive cleavage to deliver the desired aryl-
alkyl product.5 Although these reactions have achieved
delightful progress, some limitations and challenges still exist.6
First, rH-type cyclizations in an intramolecular fashion to
construct Csp3 related cyclic molecules dominate in this area.7
In sharp contrast, the intermolecular rH reactions remain much
a. College of Chemical Engineering, Zhejiang University of Technology, Hangzhou
310032, P. R. China. E-mail: liqunjin@zjut.edu.cn; xinquan@zjut.edu.cn
b. State Key Laboratory for Oxo Synthesis and Selective Oxidation, Lanzhou Institute
of Chemical Physics, the Chinese Academy of Sciences, Lanzhou 730000, P. R.
China.
Electronic Supplementary Information (ESI) available: Experimental procedures,
kinetic studies and characterization data for all compounds. See
DOI: 10.1039/x0xx00000x
Scheme 1. Pd-catalyzed coupling of 4-methylstyrene with
bromobenzene in alcohols.
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product 4a was accumulated in a small amount accompanied by
the formation of the rH product 3aa. Meanwhile, the reduction
of 4a under the same conditions with eq 1 was also performed.
The experimental results showed only trace amount of 3aa
formed. These observations strongly supported to rule out the
Yield
(%)b
Entry
1
Olefin
Product
possibility of Path a
.
58%
(3:1)
59%
(6:1)
2
3
51%
(6:1)
Scheme 2. Possible pathways of the Pd-catalyzed rH reactions.
4
5
32%c
72%d
67%
(17:1)
80
60
40
6
cyclopentane
1r
7
8
48%
16%
eq(1)-3aa
eq(1)-4a
eq(2)-3aa
cyclohexene 1s
20
0
9
Cyclooctene 1t
<5%
0
1
2
3
4
5
6
a
Reaction conditions: [PdCImPy*] (2 mol%), olefin (1 mmol), 2b
Time (h)
(1.5 mmol), KOH (2.5 mmol), 75 oC, 12 h. i-PrOH (7.0 mL).
Isolate yields of and ï[ were obtained. The ratios of and ï[ in
parentheses were determined by 1H NMR after column
b
3
3
c
d
chromatography. KOH (3.5 mmol). NMR yield was obtained
using 1,2-dibromoethane as the internal standard.
For the potential mechanism of this Pd-catalyzed rH reaction,
three possible pathways were proposed (Scheme 2). Alkene
Figure 1 . Mechanism experiments. (A) Kinetic profiles of eq (1)
and eq (2). (B) Deuterium labeling experiment.
insertion to Ar-Pd-X species produces the key intermediate
which is prone to release H-Pd-X species. Subsequently, the
normal Heck product is obtained through the facile -H
I,
Moreover, a deuterium labeling experiment applying 1a and
2i in (CD3)2CDOD was carried out, providing 3ai-d in 63% yield
with 98% deuterium incorporation. In contrast, no reaction
occurred when t-BuOH was used as the solvent. Furthermore,
when the reaction was performed in (CH3)2CHOD, 3ai without
deuterium incorporation was obtained in 67% yield (Figure 1, B).
These results exclude the possibility that the solvent serves as
proton source (Path b). Therefore, Path c is the most plausible
pathway for this reaction, in which i-PrOH is a reductant serving
b
elimination step. If the resulted Heck product is reduced under
the Pd/i-PrOH conditions, the targeted saturated rH product will
be generated (Scheme 2, Path a).10e, 21 The second possible
route involves that the intermediate
I undergoes direct
protonolysis in the presence of i-PrOH to give the desired
product (Scheme 2, Path b).22 The third possibility involves that
the alcoholysis of the intermediate
I under strongly basic
environment followed by -H elimination results in the
b
as a hydride donor through the b-H elimination process. It is
formation of Csp3-Pd-H species III, which will finally undergo
reductive elimination to produce the reductive hydroarylation
product (Scheme 2, Path c).23 To evaluate the above mentioned
three possible pathways, further experiments were carried out.
The Heck product was always observed either changing olefin
and aryl bromide or modification of the reaction conditions,
Path a seems like the most possible pathway. Under the
standard conditions, the reaction of 1a with 2a (eq 1) was
carefully investigated. As shown in Figure 1 (A), the normal Heck
noteworthy that slightly higher temperature (90 oC) and
extended reaction time (18 h) were needed for the deuterium
labeling experiment, revealing that the alcoholysis by alcohol or
the following b-H elimination is likely the rate-limiting step in
the catalytic cycle.
In conclusion, we have developed an efficient protocol to
construct Csp2-Csp3 bonds through
a
Pd-catalyzed
intermolecular reductive Heck reaction, in which inactivated
olefins and aryl bromides are reductive coupled using i-PrOH as
the reductant. The geometry-constrained iminopyridyl ligand
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plays an important role in stabilization of the catalytically active
Pd centers. Various substituents on styrene derivatives exhibit
good tolerance to react with varied aryl bromides with excellent
linear selectivity. Aliphatic olefins are also suitable partners
while giving the mixtures of linear and branched isomers.
Mechanistic studies suggest that i-PrOH is the reductant
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are ongoing in our group.
The authors gratefully acknowledge the National Natural
Science Foundation of China (21773210, 21603190, 21473160,
and 21376224). Jin also thanks the support from Zhejiang
University of Technology and Qianjiang Scholar Program funded
by Zhejiang Province.
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Conflicts of interest
There are no conflicts to declare.
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