Nickel-Catalyzed Reductive Arylalkylation via a Migratory Insertion/Decarboxylative Cross-Coupling Cascade

Article abstract of DOI:10.1021/acs.orglett.9b02870

Reported is a nickel-catalyzed reductive arylalkylation of unactivated alkenes tethered to aryl iodides with redox active N-hydroxyphthalimide esters as the alkyl source through successful merging of migratory insertion and decarboxylative cross-coupling in a cascade. This new method avoids the use of pregenerated organometallic reagents and thus enables the synthesis of diverse benzene-fused carbo- and heterocyclic compounds with high tolerance of a wide range of functional groups.

Full text of DOI:10.1021/acs.orglett.9b02870

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Nickel-Catalyzed Reductive Arylalkylation via a Migratory Insertion/
Decarboxylative Cross-Coupling Cascade
Youxiang Jin,† Haobo Yang,‡ and Chuan Wang*,†
†Hefei National Laboratory for Physical Science at the Microscale, Department of Chemistry, Center for Excellence in Molecular
Synthesis, University of Science and Technology of China, 96 Jinzhai Road, Hefei, Anhui 230026, P.R. China
‡School of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, P.R.
China
S
* Supporting Information
ABSTRACT: Reported is a nickel-catalyzed reductive arylalkylation of unactivated alkenes tethered to aryl iodides with redox
active N-hydroxyphthalimide esters as the alkyl source through successful merging of migratory insertion and decarboxylative
cross-coupling in a cascade. This new method avoids the use of pregenerated organometallic reagents and thus enables the
synthesis of diverse benzene-fused carbo- and heterocyclic compounds with high tolerance of a wide range of functional groups.
Scheme 1. (A) Redox-Neutral Arylalkylation; (B) Reductive
Arylalkylation Using Alkyl Bromides; (C) Reductive
Arylalkylation Using NHP Esters
atalytic dicarbofunctionalization of unactivated alkenes is
Ca powerful tool to rapidly increase the molecular
complexity from simple precursors by allowing the installation
of two carbon moieties across an olefinic unit. The majority of
these reactions are realized by applying a redox-neutral strategy
in which an organohalide and an organometallic reagent are
utilized as the carbon sources.1−3 Moreover, there is one
example of oxidative dicarbofunctionalization of unactivated
olefins, enabling the introduction of two identical aryl groups
through the use of organostannes.4 Despite the tremendous
progress in this territory, dicarbofunctionalization using
reactive organometallics is plagued by two intrinsic issues,
the low functional group compatibility and the additional step
for pregeneration of organometallic precursors. On the
contrary, reductive dicarbofunctionalization employing only
electrophilic organohalides as the coupling partners with
olefins is more advantageous concerning step economy and
functional group compatibility.5−7
Arylalkylation of tethered olefin can provide an efficient
access to a variety of benzene-fused cyclic compounds. For
instance, Fu and Cong reported a Ni-catalyzed redox-neutral
arylalkylation involving aryl borane as the nucleophilic carbon
source (Scheme 1A).2b Recently, our group developed a
reductive strategy for two-component arylalkylation between
primary alkyl bromides and aryl bromides incorporating a
pendant olefinic unit (Scheme 1B).5j,k However, alkyl halides,
particularly iodides, are less desirable from the viewpoint of
stability, toxicity, and availability. In comparison to alkyl
halides, alkanoic acids are more stable, less toxic, and available
from both natural and synthetic sources and, thus, are
considered as superior coupling partners. Although carboxylic
acids and their derivatives find wide applications as surrogate
of alkyl halides in decarboxylative cross-coupling reactions,8−10
application of these compounds as a component in
dicarbofunctionalization of unactivated alkenes is still elusive.11
Received: August 14, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02870
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Variation of the Reaction Parameters for the Ni-Catalyzed Reductive Arylalkylation Reaction
b
b
b
b
b
entry
variation from the optimal conditions
yield of 3a (%)
yield of 3a-1 (%)
yield of 3a-2 (%)
yield of 3a-3 (%)
yield of 3a-4 (%)
c
1
none
71 (68)
6
0
9
0
6
0
0
0
2
bromo-analogue of 1a used
L2 instead of L1
0
3
19
9
21
0
4
0
4
L3 instead of L1
trace
16
0
0
0
5
L4 instead of L1
trace
11
0
4
trace
trace
0
0
6
L5 instead of L1
45
13
0
0
7
NiBr2 instead of NiBr2·diglyme
NiI2 instead of NiBr2·diglyme
Ni(COD)2 instead of NiBr2·diglyme
DMA instead of THF
NMP instead of THF
1,4-dioxane instead of THF
toluene instead of THF
Mn instead of Zn
trace
trace
17
0
8
0
0
0
0
9
trace
8
trace
trace
trace
17
0
trace
trace
trace
2
0
10
11
12
13
14
15
16
17
32
30
45
0
29
trace
7
16
0
0
0
0
14
18
11
4
6
trace
5
0
without ZnI2
49
15
9
0
20 °C instead of 40 °C
60 °C instead of 40 °C
53
6
0
58
6
12
7
0
a
Unless otherwise specified, reactions were performed on a 0.2 mmol scale of aryl iodide 1a with 2 equiv of NHP ester 2a, 15 mol % of NiBr2·
b
diglyme2, 15 mol % of ligand L1, 4 equiv of Zn as reductant and 1.5 equiv of ZnI2 as additive in 0.5 mL THF at 40 °C for 10 h. GC yields using n-
dodecane as an internal standard. Yield of the isolated product.
c
In this context, we report the successful use of redox-active N-
hydroxyphthalimide (NHP) esters as the alkyl source in the
Ni-catalyzed reductive arylalkylation of tethered olefins, which
proceeds in a migratory insertion/decarboxylative cross-
coupling cascade (Scheme 1C).
in toluene (entry 13). Replacing Zn by Mn as reductant gave
rise to a diminished yield (entry 14). The reaction still
proceeded without ZnI2, albeit in relatively low efficiency
(entry 15). Moreover, the studied reaction was also carried out
at 20 °C and 60 °C, respectively, providing no better results in
either case (entries 16 and 17).
For optimization of the reaction conditions, we used the
iodobenzene 1a tethering a terminal olefinic unit and the
nonanoic acid NHP ester 2a as benchmark substrates (Table
1). After extensive examination of the reaction parameters, we
successfully identified the optimal conditions: NiBr2·diglyme/
L1 as catalyst, Zn as reducing agent, and ZnI2 as additive in
THF at 40 °C (entry 1). Concerning the conversion of the
tethered olefin 1a, the formation of one or more of the
following byproducts was observed under various conditions,
which are the dimer compound 3a-1, the reductive Heck
product 3a-2, the deiodination product 3a-3, and the cross-
coupling product 3a-4. Remarkably, under the optimal
conditions the bromo analogue of 1a remained intact (entry
2). The reactions employing other pyridine-based ligands L2−
L5 proceeded with lower yields (entries 3−6). NiBr2 and NiI2
were not able to promote the desired reaction possibly due to
their low solubility in THF (entries 7 and 8), while a low yield
was achieved in the case of Ni(COD)2 as the catalyst (entry 9).
Conducting the reaction in DMA and NMP afforded no
improved results (entries 10 and 11). Notably, in these cases
the cross-coupling reaction turned out to be the main reaction.
Furthermore, performing the reaction in 1,4-dioxane resulted
in a lower conversion (entry 12), whereas no reaction occurred
With the optimal reaction conditions in hand, we
commenced examining the substrate spectrum of both tethered
alkenes 1 and alkyl NHP esters 2 (Scheme 2). First, an array of
primary alkyl NHP esters were reacted with the aryl iodide 1a,
furnishing various indanes 3a−o in moderate to good yields.
Good compatibility of diverse functional moieties including
indole (3i), ester (3j), ketone (3k), carbamate (3l), halides
(3m and 3n), and alcohol (3o) was observed in this Ni-
catalyzed reaction. Notably, the reaction using the NHP ester
with a primary bromide as substrate proceeded with complete
chemoselectivity (3n). To our delight, secondary NHP esters
were also successfully utilized as the coupling partners (3p−s),
demonstrating a broader substrate spectrum than our
previously reported arylalkylation using alkyl bromides.5j,k
However, no desired product was obtained in the case of
tertiary and benzyl NHP esters as precursors.12 Subsequently,
the influence of the geometry and substitution of the olefinic
unit on this Ni-catalyzed reaction was surveyed. The reaction
using geminal disubstituted olefins as substrates afforded the
products 3t−z in moderate to good efficiency. When 1,1,2-
trisubstituted alkenes with a low E/Z ratio (ca. 1:1) were
employed as precursors, the corresponding products 3aa and
B
DOI: 10.1021/acs.orglett.9b02870
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a b
,
Scheme 2. Evaluation of the Substrate Scope for the Ni-Catalyzed Arylalkylation Reaction
a
Unless otherwise specified, reactions were performed on a 0.2 mmol scale of aryl iodides 1 with 2 equiv of NHP esters 2, 15 mol % of NiBr2·
b
diglyme2, 15 mol % of ligand L1, 4 equiv of Zn as reductant, and 1.5 equiv of ZnI2 as additive in 0.5 mL of THF at 40 °C for 10 h. Yields of the
c
d
e
isolated products. Determined by 13C NMR spectroscopy. Reaction performed on 1 mmol scale. Determined by HPLC analysis.
a
Table 2. Stoichiometric Reactions of the Aryl Iodides 1a with Ni Precatalysts Followed by Quenching with Water
b
b
b
b
b
entry
condition
additive
t (h)
recovered 1a (%)
yield 3a-1 (%)
yield 3a-2 (%)
yield 3a-3 (%)
yield 3a-5 (%)
c
1
Ni(COD)2
Ni(COD)2
Ni(COD)2
Ni(COD)2
NiBr2·diglyme
NiBr2·diglyme
NiBr2·diglyme
1
1
1
10
1
10
3
25
21
99
39
93
0
33
48
trace
6
0
49
19
13
trace
47
0
31
7
9
trace
7
7
11
11
16
8
0
1
0
2
3
4
5
6
7
ZnI2
ZnI2
9
6
ZnI2
0
16
67
a
Unless otherwise specified, reactions were performed on a 0.2 mmol scale of aryl iodide 1a, 1 equiv of Ni-precatalyst, 1 equiv of ligand L1, 4 equiv
b
c
of Zn as reductant, and 1.5 equiv of additive in 0.5 mL of THF at 40 °C. GC yields using n-dodecane as an internal standard. Reaction was
performed without Zn.
C
DOI: 10.1021/acs.orglett.9b02870
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
3ab were still obtained in good yields and excellent
diastereoselectivities. Unfortunately, the reactions using 1,2-
disubstituted and monosubstituted alkenes failed to yield the
desired products due to the high propensity to undergo β-
hydride elimination.12 Furthermore, our method is also
applicable for the synthesis of benzene-fused hetereocyclic
compounds including dihydrobenzofuran (3ae−ag), isochro-
man (3ah), indoline (3ai and 3aj), and tetrahydroisoquinoline
(3ak and 3al), which were obtained in moderate to good
yields. Notably, both the electron-withdrawing and -donating
substitutions of the aryl iodides were well tolerated (3ac, 3ad,
3af, and 3ag). In addition, we attempted to approach
compounds bearing a 7- or 8-membered ring using this
method. However, only direct cross-coupling products were
obtained in these cases.12
cascade consisting of a migratory insertion and the following
decarboxylative coupling.
Scheme 3. Sequential Stoichiometric Reaction of Iodide 1a
and NHP Ester 2j
Furthermore, the reaction between the active NHP ester 2h
and (3-methylbut-3-en-1-yl)benzene was conducted under the
standard reaction conditions (Scheme 4). In this case, the
A few control experiments were performed in order to
investigate the mechanism of this annulation reaction. First, we
found that Zn powder does not react with the aryl iodide 1a
under the standard reaction conditions to form the
corresponding organozinc reagent, which excludes the reaction
pathway initiated by transmetalation between the arylzinc and
a Ni species.13
Scheme 4. Reaction between NHP Ester 2h and (3-
Methylbut-3-en-1-yl)benzene
Next, we carried out the stoichiometric reactions between
the aryl iodide 1a and Ni precatalysts under various conditions
to explore the possible reaction pathway, which starts with
oxidative addition (Table 2). The reaction of 1a with
Ni(COD)2 in the absence of Zn provided the reductive
Heck product 3a-2 after quenching with water in a moderate
yield, indicating the feasibility of a cascade consisting of the
oxidative addition of aryl iodide to a Ni(0) species and the
following intramolecular Ni(II)-mediated migratory insertion
(entry 1). The other products in this case include the dimer
3a-1, the deiodination product 3a-3, and the 6-endo cyclization
product 3a-5, which was not observed in the catalytic
reactions. The 6-endo cyclization might be mediated by an
aryl radical, which is formed via disproportionation of the aryl
Ni(II) species formed via oxidative addition.14 Conducting this
stoichiometric reaction in the presence of Zn gave a similar
product profile in which the formation of 3a-5 was slightly
disfavored (entry 2). Surprisingly, adding ZnI2 to the reaction
mixture slowed the reaction between the aryl iodide 1a and
Ni(0) significantly (entries 3 and 4). More importantly,
inhibition of the formation of 3a-1 and 3a-5 was observed in
this case (entry 4). On the contrary, the stoichiometric
reaction using NiBr2·diglyme proceeded very sluggishly in the
absence of ZnI2 and the full conversion required extended
reaction time (entries 5 and 6), while an increase of the
reaction rate was observed by employing ZnI2 as additive
(entry 7). In comparison to the reactions using Ni(COD)2, the
formation of 5-exo ring-closing product 3a-2 was apparently
favored in this case. The results aforementioned can be
explained through the postulation that the Ni(II) species
generated through oxidative addition is first reduced to a Ni(I)
species prior to the migratory insertion favoring the 5-exo
cyclization. The reduction of Ni(II) to Ni(I) might be
accelerated by the bridging of polarized iodide anion between
Ni and Zn species in the electron-transfer process.15
decarboxylative product was afforded in 31% yield, while the
hydroalkylation reaction did not occur. This result argues
against a possible reaction pathway for the Ni-catalyzed
arylalkylation reaction, which is initiated by a radical addition
of an alkyl radical generated through decarboxylation to the
olefinic unit of tethered aryl iodides.16
We have also studied the asymmetric version of this Ni-
catalyzed arylalkylation reaction involving decarboxylative
coupling, and the preliminary investigations demonstrated
that a high enantiomeric excess could be achieved by
employing the chiral BOX L6 as ligand (Scheme 5).
Scheme 5. Asymmetric Ni-Catalyzed Reductive
Arylalkylation involving Decarboxylative Coupling
In summary, we described a Ni-catalyzed reductive
dicarbofunctionalization of unactivated alkenes tethered to
aryl iodides with a series of primary and secondary redox active
NHP esters, providing access to prepare diverse benzene-
annulated cyclic compounds, such as indanes, tetrahydroiso-
quinolines, indolines, dihydrobenzofurans, and isochromans
containing a quaternary carbon center. A good tolerance of a
broad range of functional moieties was achieved in this method
through avoidance of the use of pregenerated organometallic
reagents. Relying on the results of a series of control
experiments, we proposed a plausible reaction mechanism
Subsequently, upon full conversion of 1a in the stoichio-
metric reaction with NiBr2·diglyme we added the NHP ester 2j
instead of water to the reaction mixture, affording the
arylalkylation product 3j in a 20% yield (Scheme 3). The
result of this sequential reaction confirmed the viability of a
D
DOI: 10.1021/acs.orglett.9b02870
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b02870.
Representative experimental procedures and necessary
characterization data for all new compounds (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: chuanw@ustc.edu.cn.
ORCID
Chuan Wang: 0000-0002-9219-1785
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work is supported by National Natural Science
Foundation of China (Grant No. 21772183), the Fundamental
Research Funds for the Central Universities
(WK2060190086), “1000-Youth Talents Plan” start-up fund-
ing, as well as the University of Science and Technology of
China.
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